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Covid-19 Small Molecule Therapies Reviewed

Update: for clinical trial results as of March 18 on some of these, see here).

Let’s take inventory on the therapies that are being developed for the coronavirus epidemic. Here is a very thorough list of at Biocentury, and I should note that (like Stat and several other organizations) they’re making all their Covid-19 content free to all readers during this crisis. I’d like to zoom in today on the potential small-molecule therapies, since some of these have the most immediate prospects for use in the real world.

The ones at the front of the line are repurposed drugs that are already approved for human use, for a lot of obvious reasons. The Biocentury list doesn’t cover these, but here’s an article at Nature Biotechnology that goes into detail. Clinical trials are a huge time sink – they sort of have to be, in most cases, if they’re going to be any good – and if you’ve already done all that stuff it’s a huge leg up, even if the drug itself is not exactly a perfect fit for the disease. So what do we have? The compound that is most advanced is probably remdesivir from Gilead, at right. This has been in development for a few years as an RNA virus therapy – it was originally developed for Ebola, and has been tried out against a whole list of single-strand RNA viruses. That includes the related coronaviruses SARS and MERS, so Covid-19 was an obvious fit.

The compound is a prodrug – that phosphoramide gets cleaved off completely, leaving the active 5-OH compound GS-44-1524. It mechanism of action is to get incorporated into viral RNA, since it’s taken up by RNA polymerase and it largely seems to evade proofreading. This causes RNA termination trouble later on, since that alpha-nitrile C-nucleoside is not exactly what the virus is expecting in its genome at that point, and thus viral replication is inhibited.

There are five clinical trials underway (here’s an overview at Biocentury). The NIH has an adaptive-design Phase II trial that has already started in Nebraska, with doses to be changed according to Bayesian readouts along the way. There are two Phase III trials underway at China-Japan Friendship Hospital in Hubei, double-blinded and placebo-controlled (since placebo is, as far as drug therapy goes, the current standard of care). And Gilead themselves are starting two open-label trials, one with no control arm and one with an (unblinded) standard-of-care comparison arm. Those might read out first, depending on when they get off the ground, but will be only rough readouts due to the fast-and-loose trial design. The two Hubei trials and the NIH one will add some rigor to the process, but I’m not sure when they’re going to report. My personal opinion is that I like the chances of this drug more than anything else on this list, but it’s still unlikely to be a game-changer.

There’s an RNA polymerase inhibitor (favipiravir) from Toyama, at right, that’s in a trial in China. It’s a thought – a broad-spectrum agent of this sort would be the sort of thing to try. But unfortunately, from what I can see, it has already turned up as ineffective in in vitro tests. The human trial that’s underway is honestly the sort of thing that would only happen under circumstances like the present: a developing epidemic with a new pathogen and no real standard of care. I hold out little hope for this one, but given that there’s nothing else at present, it probably should be tried. As you’ll see, this is far from the only situation like this.

One of the screens of known drugs in China that also flagged remdesivir noted that the old antimalarial drug chloroquine seemed to be effective in vitro. It had been reported some years back as a possible antiviral, working through more than one mechanism, probably both at viral entry and intracellularly thereafter. That part shouldn’t be surprising – chloroquine’s actual mode(s) of action against malaria parasites are still not completely worked out, either, and some of what people thought they knew about it has turned out to be wrong. There are several trials underway with it at Chinese facilities, some in combination with other agents like remdesivir. Chloroquine has of course been taken for many decades as an antimalarial, but it has a number of liabilities, including seizures, hearing damage, retinopathy and sudden effects on blood glucose. So it’s going to be important to establish just how effective it is and what doses will be needed. Just as with vaccine candidates, it’s possible to do more harm with a rushed treatment than the disease is doing itself

There are several other known antiviral drugs are being tried in China, but I don’t have too much hope for those, either. The neuraminidase inhibitors such as oseltamivir (better known as Tamiflu) were tried against SARS and were ineffective; there is no reason to expect anything versus Covid-19 although these drugs are a component of some drug cocktail trials. The HIV protease therapies such as darunavir and the combination therapy Kaletra are in trials, but that’s also a rather desperate long shot, since there’s no particular reason to think that they will have any such protease inhibition against what this new virus has to offer (and indeed, such agents weren’t much help against SARS in the end, either). The classic interferon/ribavirin combination seems to have had some activity against SARS and MERS, and is in two trials from what I can see. That’s not an awful idea by any means, but it’s not a great one, either: if your viral disease has interferon/ribavirin as a front line therapy, it generally means that there’s nothing really good available. No, unless we get really lucky none of these ideas are going to slow the disease down much.

There are a few other repurposed-protease-inhibitors ideas out there, such as this one. (Edit: I had seen this paper but couldn’t track it down, so thanks to those who sent it along). This paper suggests that the TMPRSS2 protease is important for viral entry on the human-cell-side of the process, a pathway that has been noted for other coronaviruses. And it points out that there is a an approved inhibitor (in Japan) for this enzyme (camostat), so that would definitely seem to be worth a trial, probably in combination with remdesivir.

That’s about it for the existing small molecules, from what I can see. What about new ones? Don’t hold your breath, is all I can say. A drug discovery program from scratch against a new pathogen is, as many readers here well know, not a trivial exercise. As this Bloomberg article details, many such efforts in the past (small molecules and vaccines alike) have come to grief because by the time they had anything to deliver the epidemic itself had passed. Indeed, Gilead’s remdesivir had already been dropped as a potential Ebola therapy.

You will either need to have a target in mind up front or go phenotypic. For the former, what you’d see are better characterizations of the viral protease and more extensive screens against it. Two other big target areas are viral entry (which involves the “spike” proteins on the virus surface and the ACE2 protein on human cells) and viral replication. To the former, it’s worth quickly noting that ACE2 is so much unlike the more familiar ACE protein that none of the cardiovascular ACE inhibitors do anything to it at all. And targeting the latter mechanisms is how remdesivir was developed as a possible Ebola agent, but as you can see, that took time, too. Phenotypic screens are perfectly reasonable against viral pathogens as well, but you’ll need to put time and effort into that assay up front, just as with any phenotypic effort, because as anyone who does that sort of work will tell you, a bad phenotypic screen is a complete waste of everyone’s time.

One of the key steps for either route is identifying an animal model. While animal models of infectious disease can be extremely well translated to human therapy, that doesn’t happen by accident: you need to choose the right animal. Viruses in general (and coronaviruses are no exception) vary widely in their effects in different species, and not just across the gaps of bird/reptile/human and the like. No, you’ll run into things where even the usual set of small mammals are acting differently from each other, with some of them not even getting sick at all. This current virus may well have gone through a couple of other mammalian species before landing on us, but you’ll note that dogs (to pick one) don’t seem to have any problem with it.

All this means that any new-target new-chemical-matter effort against Covid-19 (or any new pathogen) is going to take years, and there is just no way around that. Update: see here for just such an effort to start finding fragment hits for the viral protease. This puts small molecules in a very bimodal distribution: you have the existing drugs that might be repurposed, and are presumably available right now. Nothing else is! At the other end, for completely new therapies you have the usual prospects of drug discovery: years from now, lots of money, low success rate, good luck to all of us. The gap between these two could in theory be filled by vaccines and antibody therapies (if everything goes really, really well) but those are very much their own area and will be dealt with in a separate post.

Either way, the odds are that we (and I mean “we as a species” here) are going to be fighting this epidemic without any particularly amazing pharmacological weapons. Eventually we’ll have some, but I would advise people, pundits, and politicians not to get all excited about the prospects for some new therapies to come riding up over the hill to help us out. The odds of that happening in time to do anything about the current outbreak are very small. We will be going for months, years, with the therapeutic options we have right now. Look around you: what we have today is what we have to work with.

161 comments on “Covid-19 Small Molecule Therapies Reviewed”

  1. Xiben says:

    For Remdesivir, it didn’t go all the way to 5-OH. Instead it will form the mono-phosphorylated compound. Usually the first phosphorylation of 5-OH is quite slow. Remdesivir solved this problem.

    1. bofh453 says:

      Yep, precisely this — it’s the same general principle as with sofosbuvir, & even a very similar solution to this problem in the end as well.

    2. Xiben says:

      It should be this paper, figure 1.

    3. A cure for cats too!

  2. Some Dude says:

    There is this very recent cell paper:
    where they propose that “Camostat mesylate” might work and is “clinically proven”, whatever that means.

    1. Derek Lowe says:

      I kept looking for that one; I knew I’d seen something like that the other day! Just added to the post.

      1. Wasn’t that in micromolar concentrations? Seems weak.

        1. milkshake says:

          EC50 1uM, EC90 5uM
          Nothing to rave about but camostat is safely dosed 100mg three times a day after meal. Maybe it could be use as prophylactic measure, at least for people working with coronavirus patients

        2. Frank17 says:

          Perhaps HCQ (enveloped) could be administered in liposomes by inhalation at much lower doses than in systemic therapy (or supplementing it), thereby reducing side effects and risks, perhaps the HCQ concentration in the lysosome would then be sufficient to achieve an antiviral effect. One could imagine a clathrin-mediated endocytosis. Is anyone aware of studies on this?

      2. Nela Gudelj says:

        What about this zoo connection, I found this article fascinating

    2. Pejman Soroosh says:

      According to the instruction of ONO, the peak drug concentration in plasma is only 40 ng/ml. 40ng/ml is about 80 nM (physiological dose). In the Cell paper, the authors used Camostat at 10 micro M, which is 200-times higher than physiological dose. I suspect clinical effect in terms of dose.

  3. cb says:

    Why do these nice algorithms for machine learning do not suggest dimethyl-fumarate (Tecfidera) as possible repurposed drug. On the one hand this drug (and its metabolite: mono-methyl ester) is a well known thiophilic Michael acceptor which should inhibit the papaine-like protease and on the other hand this drug would reduce IL-6 induced lung inflammation.

    1. cb says:

      The MS drug dimethyl fumarate indeed could work for repurposing covid 19:

  4. 3Cpro says:

    There may be coronavirus 3CLP (3C-like cysteine protease) inhibitors sitting on the shelves of pharma/biotech that are worth revisiting. In the past, direct-acting anti-virals for picornaviruses, including the common cold, included 3C protease inhibitor programs. The high degree of protein and substrate homology between 3CP and 3C yields rhinovirus inhibitors that can also target coronavirus. Since the common cold is relatively benign, and by the time you’re symptomatic, your immune system is well along the way to clearing the infection (with plenty of rest and fluids), it was hard sell for development by pharma. Since Covid-19 is not benign maybe this will provide an impetus to dust off the shelves of pharma.

    1. Save the World says:

      Is there a screening system for Covid-19 to check the activity of small molecule/peptide? OR We have screened using luciferase activity (?) targeting PLPro or 3CLpro. We could not find a screening system. If you share your views regarding the screening system it will be highly appreciated. Thank you,

      1. 3Cpro says:

        To my knowledge there’s not a coronavirus replicon assay, but you can screen for cellular protection, which tracks pretty well with protease inhibition – e.g. see Table 3 of WO2018042343. Also take a look at the more recent publication in Science though the potency of the compounds reported is marginal for SARS-CoV-2. However, the trick for protease inhibitors like this isn’t necessarily potency, but oral exposure and metabolic stability.

  5. Calvin says:

    I posted this before, but Remdesivir was originally came from a Gilead RSV project which was then tested against Ebola with a bunch of other compounds with a similar mechanism (JnJ did the same for their RSV nucs but found they weren’t as good). It looks absolutely great preclinically in Ebola, but was way less impressive in patients (compared to two other antibodies). The general guess seems to be that it only works if given early during infection. That’s not uncommon for acute viral infections.

    Most of the other compounds here were trotted out for Ebola too, but their activity is generally more about tox than anything that could be tied to them being genuinely active against the virus. What “activity” there is is so low that I doubt you could get to a dose that would be clinically relevant.

    Interferon will probably have some efficacy but it’s nasty nasty stuff so not sure I’d recommend it.

    The Gilead compound stands a decent chance of having an impact if it can be given early enough to patients. Otherwise, the other compounds are largely a waste of time.

    1. MedChemist says:

      I agree antiviral therapies are often only effective if given very early, eg Tamiflu. While Influenza is usually over after 1-2 weeks, covid-19 seems to take 3-4 weeks in severe cases, hopefully there is enough time for Remdesivir to speed up recovery. Let’s keep fingers crossed!

      1. MedChemist says:

        If one person is diagnosed with COVID-19, one could start treating all contact persons with Remdesivir immediately, especially the high risk and elderly contacts. So treatment could start very early on in the disease.

        1. milkshake says:

          remdesivir is infusion, it is not something you would want as a prevention agent. But Camostat is a pill, given 3 times a day, and seems quite safe over extended period

          1. ANON says:


            I would not have expected a benzamidine to have a good chance to have useful oral bioavailability, but you’re right!

  6. Giannis Zaxarioudakis says:

    How about biologics like hACE2-Fc. There are some preprints that claim they work amazingly well. Producing biologics had become much cheaper than it used to. Now it costs around $70 per gram. And one dose should protect a person for a month

    1. Derek Lowe says:

      Biologics are coming up in the next installment. . .

      1. G Marquez says:

        Not so long ago GSK completed a Phase 2 study with rhACE2 for ARDS. It looks like the program was discontinued, curious how useful will be in this setting

  7. Luckless Pedestrian says:

    It’s also important to remember that in general, antiviral drugs targeting acute respiratory viral infections have not proven to be terribly useful for treating patients with full-blown symptomatic infections. That could be different for covid-19, of course, but drugs like oseltamavir and palivizumab have very limited ability to alter the course of disease or reduce symptoms in people with entrenched infections with influenza and RSV, respectively. They do work remarkably well when taken prophylactically or soon after infection. This is something that should be considered carefully when designing clinical trials of putative anti-covid-19 agents.

    1. MadChemist says:

      True, it may in fact be more beneficial to target the inflammatory processes rather than the virus itself…

  8. Giannis Zaxarioudakis says:

    I think the consensus is that in severe condition patients the vast majority of damage is caused by cytokine storms. These are supposed (at least partially) mediated by IL-6. Besides the biologics that inhibit IL-6 there are multiple JAK kinase inhibitors for the treatment of immune diseases. These might also work to limit the damage caused by the immune system but with less effect on antibody production that is essential at stopping viral replication.

    1. Cathy Tralau-Stewart says:

      We should be looking at the range of anti inflammatory approaches and tools we now have for these pathways in these patients. I heard some discussion that inhaled steroids exacerbate the inflammation response. Does anyone know any data on this?

      1. Giannis Zaxarioudakis says:

        There are some anecdotal evidence from Japan that Ciclesonide (Alvesco) helps.

      2. Benji Vulao says:

        Lots of great data and insight in this post and the replies. I found this review from 2008, “Respiratory Viruses Other than Influenza Virus: Impact and Therapeutic Advances”(, to be an interesting read.

        This study ( indicated glycyrrhizin, aescin and reserpine derivatives, as well as ginsenoside-Rb1, active against SARS-CoV, in 2004 (so not the 2019 strain[s]), while pentoxifylline, melatonin, vitamin C, AZT, didanosine, nevirapine, ritonavir, lopinavir, saquinavir, and ribavirin were not effective. However, another study ( in 2004, found ribavirin and lopinavir effective alongside interferons, rimantadine, baicalin and glycyrrhizin.

        Nitric oxide seems to be laboratory relevant in demonstrating the difficult balance between killing the virus and destroying the epithelium through excess inflammation for which the cytokine storm seems responsible. This study (“Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway” – used TUDCA, a chemical chaperone and calpain inhibitor, in vitro, to lower cytokines and endoplasmic reticulum stress in mouse lung tissue. Various mechanisms to lower ROS, inhibit NOX2 & 4 and increase glutathione would seem helpful. Berberine comes to mind as a NOX2 inhibitor. As a purified alkaloid, it might actually have a higher bioavailability. But it also has varied side effects.

        Mentioned in the replies were ambroxol and ciclesonide. Mucolytic agents like ambroxol and things that might increase ciliary beat frequency (roflumilast, salmeterol, cordyceps, nobiletin, ATP production and alkalinity) would seem to warrant further investigation. Amboxol’s mucolytic action seems to work through calcium displacement so calcium and lower sodium ( intake, itself, might be useful? Ciclesonide and beclomethasone have higher lung deposition than other inhaled corticosteroids (

        1. Aaron J Gill says:

          In addition Korean Pasteur institute found significant anti-viral covid activity…combined with Anti-cytokinetic activity and low bioavailability outside of lungs (unique product assembles in alveoli)…awesome possibilities not just for saving lung function

        2. Krista says:

          Regarding berberine, I take 1500mg of Berberine daily to help manage PCOS. I am the only one in my family not to have developed a severe respiratory infection since February when my husband came back from Northern Italy. No confirmed cases as fortunately, no one needed hospitalization therefore no one was tested. But I did wonder at the time, having previously read this

          1. Thomas Ruddy says:

            In speaking to an Emergency Room Nurse at our local hospital, almost all the people dying of COVID19 at the hospital have Diabetes. Berberine lowers blood sugar and may be a possible answer in preventing the cytokine storm!

    2. Mark Nelson says:

      2nd generation tetracyclines such as doxycycline and minocycline affect IL-6 levels and ameliorate cytokine storms. They act at the level of mitochondria in activated immune cells and are potent anti-inflammatory agents in addition to their antibiotic activity. And they are relatively safe, been used for decades, and given the choice of full blown ARDS and death versus the remote and slim chance of developing resistance, I’d take the latter.

      1. Rae says:

        Has anyone tried doxycycline for this treatment? I know it’s the other half of the treatment for malaria, and covid is different. However doxycycline is supposed to disable mRNA to tRNA function.

        1. OC says:

          Hate to link to a NY Post article but this article about HCQ / Doxy combination therapy could be quite interesting:

          47 very high risk patients treated (nursing home patients with significant co-morbidities like hypertension, coronary artery disease, COPD and congestive heart failure that made Azithromycin a no go).

          38 have recovered. 2 passed away. 7 still in hospital.

          Doesn’t sound great but to give some perspective a nursing home in my home city has had 17 infections amongst residents. 6 have died so far (I believe there are several still fighting for life in ICU).

      2. Yarodur says:

        Unfortunately, they are not likely to be good drugs against CoVs. Minocycline has been suggested to benefit patients in several disease settings, including neurodegeneration and pancreatitis, but the trials had to stop, because it made matters worse. Apparently, it affects the cell mitochondria in undesirable way, making cells more frail. It works well against as antibiotic, but its repurposing has been unsuccessful so far. Doxycycline is more like an anti-cancer drug than an antibiotic, so even more toxic.

        1. Db says:

          The use of doxycycline as a potential prophylaxis treatment for COVID-19 may be warranted. Doxycyline
          inhibits metalloproteinases (MMPs), an group of enzymes implicated in acute respiratory distress
          syndrome (ARDS), a major complication of COVID-19.(1)
          Papain-like proteinase (PLpro) is responsible for proteolytic cleavage of the replicase polyprotein to
          release non-structural proteins 1, 2 & 3 (Nsp1, Nsp2 and Nsp3) which is essential for viral replication.(3)
          Virtual ligand screening of potential drug targets of SARS-CoV-2 showed that doxycycline ranked 6th as
          potential PLpro inhibitor.(3) Ribavirin ranked 1st overall for relative binding affinity.(3)
          3C-like main protease (3CLpro) or Nsp5 which is cleaved from the polyproteins causes further cleavage
          of Nsp4-16 and mediates maturation of Nsps which is essential in the virus lifecycle.(3) Virtual ligand
          screening showed doxycycline had high binding affinity to 3CLpro, ranking 26th overall.(3)
          Doxycycline is an ionophore (forms complexes to facilitate cell membrane transport) and binds divalent
          cations (including Zn2+).(4) Zinc has an inhibitory effect on the replication on SAR-CoV.(5) Zinc inhibits
          proper processing of replicase proteins and RNA dependent RNA polymerase (RdRp) activity.(5)There
          is a strong case for use of a zinc supplement in combination with doxycycline as an antiviral
          Therefore, doxycycline administered at a high dose of 100mg twice daily to healthcare workers or other
          patients at high risk, with a high dose zinc supplement, preferably administered 4 hours apart from the
          doxycycline dose to allow absorption (and prevent GI chelation), may be considered. The relatively
          benign side effect profile and affordability of this regimen would further support its use.

          1. Db says:

            I almost forgot to add that chloroquine is a zinc ionophore. I just wonder whether the link between doxy and chloroquine is the ability to concentrate zinc within the cell to exert it’s antiviral activity.

          2. MD-PHD says:

            Exactly this is old school chemistry you want to use a chelators, ligand or complexing agent, they are few and far between. And it is also probably why both hydroxycholorquine and minocycline has such pleuripotent effects. Sartans also interfer with zinc but in a more gentle way. The world is already out of stock with hydroxycholorquine and quinine.

            Every step and every enzymatic process for this virus needs zinc (ACE2, replicase, elastase, collagenase, co-factors, and probably more enzymes). The problem is that molecular biologist do not have clue about clinical medicine and vice versa. So there is a big black hole in the middle, as well as lack of incentive and profit.

            That is why we need to use old drugs and “nuke” the zinc enzymes until we have a more sophisticated tool or vaccine. Old drugs that stain your teeth, skin and mucosa/sclera long term (hydroxycholorquine, minocycline, doxycycline, lymecycline, tetracycline and a few more (including bisphosphonates like alendronate)) are “promiscious” molecules that bind zinc, calcium and other metals.

            So while a bit crude it will have to do for now.

            Minocycline is the most likely next candidates and why:
            -Small and lipid soluable molecule.
            -Accumulates at sites of injury.
            -Safer than hydroxycholorquine (less cardiotoxic)
            – More available?
            -Inhibitis several types if enzymes including replicase, elastase/collagenase and other MMPs.
            -Certain antiviral properties (I.e. Dengues)
            -Reduces harmful cytokines IL-6/TNF-A.

            Further adding statins would reduce viral replication as new viruses need to steal parts of membrane to have new capsule for next virus release, and drugs like atorvastatin slow this down, plus maintain homeostasis and reduces vascular/cellular damage.

            I think we can drug this virus to the ground fast this way.

          3. MK says:

            Doxycycline also kills the Wolbachia bacteria that has since been introduced into the mosquito population and also found in multiple insects of the two primary suspects diet that may have allowed the jump from animal to human since it can live within parasites that can infect humans. . Wolbachia also has the ability to carry dna from a existing cell into a new host via virus. Wolbachia also tends to be more aggressive in male species as well can lay dormant and then start a process where if the host cell starts to fight will essentially cause the host cell to start to kill itself in rapid fashion.

          4. MD-PHD says:

            Yes, minocycline also acts intracellularly, both doxycycline and minocycline was used for malaria as well in the past. And minocycline is approved in some countries for rheumatic diseases probably due to blocking zinc dependet enzymes.

          5. DB says:

            Yes I agree. Minocycline is an obvious substitute for doxycycline.
            Something that I found curious was that people were testing positive to Dengue virus who were actually NOT infected with Dengue, but were in fact positive to SARS-CoV-2.
            Now chloroquine is active against Dengue, Chicungunya and SARS-CoV-2.
            Doxy is active in vitro and in vivo against Dengue and Chicungunya.
            It’s a reach but can we extrapolate this mean doxy can also be used as an effective treatment

          6. Toni says:

            Concerning chloroquines as ionophore one has to be a bit more careful. The data of the mentioned publication looks rather artificial to me. It’s possible the intracellular zinc buildup is secondary.
            In addition, relatively moderate increase of zinc is only achieved at chloroquine concentrations that cannot be (and should not be) achieved under normal conditions.

          7. MD-PHD says:

            Minocycline is the most potent by far, but also has a bit more side effects long term but not a issue short term. Om terms of supply doxycycline is more in use and also probably easier to get access/supply to. But it is probably so old tetracycline will probably will do the same.

            Adding zinc is an idea, that probably can work as part of a home remedies (I.e. alpha-lipoic acid and acetyl-l-caritine are also molecules that can bind zinc, as well as bioflavnoids like quercetin/troxerutin. But this is a bit Linus Pauling territory and he got Nobel Prize for discovering how antibodies attach to their target. He later got interested in vitamin-C as a cure all, orthomolecular medicine and did not gain acceptance with that, he may have been on the rigth track but did not have the tools and understanding we have today. And zinc has some effect during Ebola and for some viral gastroenteritis diseases in children. But giving it with hydroxycholorquine or tetracyclines could halt uptake and is probably unecessary, so I would not mix them.

          8. tb says:

            In the Netherlands, there seems geographical overlap between areas highest affected by a previous outbreak of Q-fever, a bacterial infection coming from sheep, cattle and goats that can cause pneunomia, and Covid19 (See maps

            Obviously this might be a coincidence, but maybe it is an idea for further research. It could be that people there with untreated Q fever are a risk group. Would it even be possible Q-fever was also present in the highly affected rural areas in Northern Italy?
            Q fever medicines are Doxycyline and hydrocholoroquine. Like in Covid-19 men have more symptoms in Q fever. Might Doxycyline and hydrocholoroquine be effective for these groups or in general?

          9. The oral route using a Zinc ionophore seems to have a lot of promise, Hinokitiol is a prominent Zinc Ionophore that the Japanese have been using as a food additive for years and is in itself anti-viral, having been used as a natural disinfectant against SARS-COV (Not current strain) at a concentration of just 0.2%.
            These guys have gone ahead and put it into a consumer oral spray
            I would be interested if anyone has some real world data on the spray effectiveness.

        2. MD-PHD says:

          Here is reveiw article on tetracyclines:

          And it seems like giving tetracyclines with fluconazole (Diflucan) enhances their ability to bind some of these zinc enzymes perhaps by making the space smaller.

  9. Sam says:

    Just to get the scientific vocabulary right: COVID-2019 is the disease caused by the current coronavirus. The virus itself is called SARS-CoV-2, where COVID-2019 stands for Coronavirus disease from 2019, SARS-CoV-2 stands for Severe Acute Respiratory Syndrome CoronaVirus 2

    You are talking about the pathogen COVID-2019, but of course you mean the pathogen SARS-Cov-2.

  10. DTX says:

    Sam – Thanks, I didn’t realize this. Your post made me want to find references on the terminology. A question in a FAQ from CDC illustrates your point.

    CDC’s question: “Is SARS-CoV-2 (the virus causing COVID-19) the same as the MERS-CoV or SARS-CoV?”

    WHO states this as well: (however, I rely little on WHO regarding this whole subject. WHO seems very passive & primarily focused on politics, not health).

    1. carlamr says:

      totally agree

  11. rtah100 says:

    Covid-19 is like a small molecule Glastonbury, including some famous names having a comeback. Thalidomide has got some press, being prescribed for patients with ARDS for its twin anxiolytic and immune-modulating properties. The anxiolytic is important to help patients relax their breathing on a ventilator….

    There have also been some articles reminding the world of the power of iodine (Lugol’s solution) as a viricide. Sufficiently non toxic to spray around, improves mask protection on the mask and even recommended as a dietary supplement to increase plasma levels of iodine. Just watch out for temporary thyroid derangement!

  12. Barry says:

    Treatments aimed at the life-threatening cytokine storm (IL-6 blockers?) might be co-administered with passive gamma globulin therapy. It’s old-fashioned and not as cost-effective as a vaccine eventually, but it might be implemented faster

  13. paul_z says:

    Nicotianamine (a simple molecule contained soybeans) is a pretty strong ACE2 inhibitor (IC50 = 84 nM). Judging by the structure it may not survive in the digestive tract but may be good for inhalation.

  14. Dahlene says:

    What about interferon as a prophylactic?
    We should assume that SARS CoV-2 subverts IFN at STAT1/2, like many viruses, but earlier IFN could activate the distal IFN effectors.
    The problem would be when to stop dosing (and toxicities).

    1. MD-PHD says:

      Interferon (as well cortisone and ribavirin) have all been shown to be associated with previous studies. So while in theory it sounds nice it does not work in real life.
      Interferon’s could amplify or make the cytokine storm worse. (While blocking certain interleukines like IL-6 seems better strategy). And it seems like the immunesystem reach a point of no return (when it activated and cortisone does not affect these “kamikaze” parts of the immuncelles/immunesystem they have already been launched to attack.

  15. Luis says:

    The International Society for Antiviral Research has published a webpage with a list of curated links about SARS CoV-2 and COVID-19 with a special emphasis on antivirals:

  16. Rapol says:

    Has Sofosbuvir been tested for treating COVID-19?

    1. not prepared in a rich country says:

      I’d be surprised if Gilead didn’t do that?

    2. Yarodur says:

      Good question. Sofosbuvir probably needs to be administered through i.v. rather than orally in this case though.

      1. Rapol says:

        There is no question sofosbuvir can be formulated in i.v. PK study can tell whether oral works. It should be put to test for SARS-CoV-2.

  17. Amanda says:

    I am not an expert by any stretch of the imagination, but my family have been taking elderberry syrup this cold and flu season and had good luck not getting sick. I came across this article and I think an expert needs to take a look at it.

    1. Sean says:

      Isn’t it amazing how may studies of elderberries against flu virus and different kind of corona viruses, that the black elderberries show statistical to decimate the viruses.. and the “health community” is so anti-nature they can’t even try a study of black elderberries against corvid-19. Italy is running out of hospital beds, they can’t even try to turn a shop vac into a lung fluid removal device so the 80+ year olds left to die have a way to fight even if their lungs are filling up with fluid. Really pathetic show of lack of leadership by liberals and conservatives. They literally are just to stupid.

      1. Joe Psycho says:

        A lot of evidence in this case is in vitro (as does this kill viruses in a Petri dish) and does not always apply to potential as a treatment or even a lead compound. however, a few in vivo tests show some activity, isolation of potential leads may create a potential pharmacophore that could lead to the development of a semisynthetic candidate in development.

  18. Rob JM says:

    Zinc and vitamin d have also shown efficacy in reducing viral respiratory disease both in clinical studies and in vitro. Deficiency of both also results in severe immune impairment. On a molecular level zinc interferes with both viral proteases, and coronavirus polymerase. Vitamin D deficiency is correlated with ARDS development, it both stimulates the immune system while reducing inflammation.

    1. CKlein says:

      Wonder if chloroquine’s activity is related to its known ability to be a Zinc ionophore.

  19. Jane says:

    Disulfiram has shown activity against MERS and SARS, is easily available and very cheap, and deserves study in COVID 19.
    It’s been repurposed for Lyme Disease with good clinical results, and being studied at Columbia University. It was originally developed as an anti-parasitic.

    1. KT says:

      It could be an interesting drug, but there are huge worldwide problems in production and isn’t available at this moment.

    2. Yarodur says:

      The problem is, as the title “Disulfiram Can Inhibit MERS and SARS Coronavirus Papain-Like Proteases via Different Modes” suggests, disulfiram only blocks papain-like CoV proteases. They are not the main one, which makes most of the scissions and is essential – not the one, which is supposedly targeted by lopinavir. These two or three papin-like proteases (depending on particular CoV type) do only very few scissions and seem to be completely redundant. Even lipinavir is a weak drug, so it leaves a very small chance for disulfiram to be of any benefit.

    3. Yarodur says:

      Is disulfiram a dithiocarbamate? In that case it may have an inhibitory effect on the IL-6 signaling.

  20. save the humanity says:

    Sofosbuvir is the FDA approved and safe viral RNA polymerase inhibitor. Sofosbuvir can save the humanity facing death and panic of SARS-CoV-19 before vaccine is available. We are not desperate of no treatment. We are desperate of lack of imagination.

    Based on chemical structures and safety profiles, sofosbuvir is expected to be superior to Remdesvir in inhibiting SARS-Cov-19 RNA polymerase. Here are reasons:
    1. Both HCV and SARS-Cov-19 are single positive strand RNA virus. The 2 virions actually look more similar than Ebola. RNA polymerase of HCV and SARS-Cov-19 are similarly inhibited by sofosbuvir based on sequence, model, and molecular docking
    2. A Columbia University group is testing sofosbuvir and making an obligatory RNA chain terminator by blocking 3’-OH. The news was picked up by obscure journals pharmaphorum.
    3. The crucial difference of performance of nucleoside analog drugs is safety. It is very similar to gene therapy. Both use the basic molecular biology of nucleotides or nucleic acid universal to human and virus. The recent success of gene therapy compared to failures a decade ago proves the critical importance in achieving safety profiles. Among all other HCV nucleoside analogs (e.g., BMS-986094, MK-0608, and IDX184), sofosbuvir shows superb performance thanks to its safety. It achieves its therapeutic exposure or maximum concentration in human by avoid being hampered by toxicity. Structurally, the major difference is the nucleoside base in the analogs. Similar to structure of sofosbuvir, Uprifosbuvir may also work
    4. COVID-19 patients often experience hypoxemia causing irreversible organ damages. It is crucial to avoid toxicity of major organs (e.g., heart, liver, and kidney) by nucleoside analog treatment. The failure of BMS-986094 is caused by heart and kidney toxicity

    1. Yarodur says:

      Very good point. Sofobuvir share with remdesivir the same phosphonate technology of Gilead – same protective groups. It (1) masks polar hydroxyls, making drugs easily cell permeable, thus eliminating one of the barriers (2) resolves the problem of the nucleoside monophosphorylation step, which is the bottleneck for the drug to start acting. But HCV (against which sofosbuvir is licenced) and CoVs are quite different. For instance, alisporivir seems to work against HCV, but not against MERS and SARS. The next possible compilcation is the administration route. Sofosbuvir is taken orally as 400mg tablets, if I am not mistaken. Ok, if it is not destroyed (I mean all those protective groups get cleaved off) in the intestine, then almost all of sofosbuvir goes into the liver first through the portal vein. I am not sure the protective group will actually survive in the stomach with all those esterases around. I may be wrong, one needs to look at the pharmakinetics data. But anyway, remdesivir is administered i.v. in Chinese trials, and apparently at much lower doses. It is understandable, given that it needs to act in the lungs. So there may be caveats in repurposing sofosbuvir for Covid-19. For the perspective, you may remember that the core nucleoside of remdesivir (known as GS-441524) has proved to be indispensable drug against feline infectious peritonitis (essentially caused by some cats coronovirus). It is the only effective drug against this deadly thing, and is a legend among the cat lovers (you can see it in the relevant FIP groups on Facebook). So it may be that sofosbuvir would not match remdesivir’s efficiency. But it may be very useful still. After all, according to some news reports, some favipiravir trial against Covid-19 has just shown very good results. This backs your suggestion, as both favipiravir and sofosbuvir are pyrimidine-like nucleotide derivatives (as opposed to remdesivir, who is purin-like). One may even advocate for making a full protected phosphonated rybosylated version of favipiravir – in sofosbuvir-like style. I could get the benefits of both Gilead technology and that idea behind favipiravir and ribavirin (a rotating amide bond that confuses virus). Since the mechanisms of action of favipiravir/ribavirin and most other nucleotide analogues, including sofosbuvir and remdesivir, are different, they could act in synergy. So I think your idea to look into sofosbuvir is very good.

      1. Rapol says:

        Both HCV and SARS-CoV-2 rely on RNA dependent RNA polymer (RdRp). Sofosbuvir is an extent inhibitor. In addition, it is much safer than other inhibitor such as BMS-986094 that failed due to toxicity to heart and kidney. Alisporivir works on mechanisms different from RdRp. It is no surprise alisporivir works differently between the 2 viruses. The prodrug is absorbed and converted to activated triphosphate in cells. If i.v. is required for killing the virus in lung, there is no reason it cannot be formulated so.

  21. SaveHumanity says:

    Sofosbuvir is the FDA approved and safe viral RNA polymerase inhibitor. Sofosbuvir can save the humanity facing death and panic of SARS-CoV-19 before vaccine is available. We are not desperate of no treatment. We are desperate of lack of imagination.

    Based on chemical structures and safety profiles, sofosbuvir is expected to be superior to Remdesvir in inhibiting SARS-Cov-19 RNA polymerase. Here are reasons:
    1. Both HCV and SARS-Cov-19 are single positive strand RNA virus. The 2 virions actually look more similar than Ebola. RNA polymerase of HCV and SARS-Cov-19 are similarly inhibited by sofosbuvir based on sequence, model, and molecular docking

    2. A Columbia University group is testing sofosbuvir and making an obligatory RNA chain terminator by blocking 3’-OH. The news was picked up by obscure journals pharmaphorum.

    3. The crucial difference of performance of nucleoside analog drugs is safety. It is very similar to gene therapy. Both use the basic molecular biology of nucleotides or nucleic acid universal to human and virus. The recent success of gene therapy compared to failures a decade ago proves the critical importance in achieving safety profiles. Among all other HCV nucleoside analogs (e.g., BMS-986094, MK-0608, and IDX184), sofosbuvir shows superb performance thanks to its safety. It achieves its therapeutic exposure or maximum concentration in human by avoid being hampered by toxicity. Structurally, the major difference is the nucleoside base in the analogs. Similar to structure of sofosbuvir, Uprifosbuvir may also work

    4. COVID-19 patients often experience hypoxemia causing irreversible organ damages. It is crucial to avoid toxicity of major organs (e.g., heart, liver, and kidney) by nucleoside analog treatment. The failure of BMS-986094 is caused by heart and kidney toxicity

    1. SaveHumanity says:

      references:“” “” “”

  22. AnonChemist says:

    Remdesivir is nice and all but if it’s most effective when administered early I don’t think it will do much. Sure Gilead has some stockpiled, but it’s not like they’re manufacturing it commercial at all anywhere since up until now there was no indication worthy of that scale. It’ll take years to get the supply chain in place for the raw materials, do the tech transfers, validate at each supplier, do audits and on and on. There is no chance they will be making useful quantities in time the help with the pandemic before the said pandemic is winding down. It could be useful as an emergency intervention, but like Derek and other pointed out that is exactly when this type of drug would be least useful.

    Not to mention this thing looks like a complete bear to manufacture on scale. I say this as a chemist that has manufactured Gilead drugs on scale and has experience with their phosphorus chemistry. Not easy stuff!

  23. Nile says:

    “…inhaled steroids exacerbate the inflammation response”.

    If that report is true, it’s very bad news for vulnerable patients in London, where the endemic asthma from our microparticulate air pollution is managed by inhaled steroids.

    We could become the first city to experience significant COVID-19 mortality among children.

    1. wanderer says:

      Hi Nile, where did you read that inhaled steroids worsens immune response?

      Current data from China and elsewhere show that kids are almost not affected by this virus. I don’t think the air quality in London is any worse compared to Chinese cities.

      1. Nile says:

        I read it in one of the comments above: “if true” is there for a reason and confirmation or debunking would be welcome.

        The atypical mortality (ie: under 60 years of age) in China is associated with pre-existing lung damage: hence my concern about childhood mortality showing in cities with an unusual prevalence of asthma.

    2. Yarodur says:

      There are non-steroid preventive inhalers (Tilade and Intal). Unfortunately, If am not mistaken, they are hated by the patients, and almost disappeared from the market. Nevertheless, nedocromil (the acting substance of Tilade) seems to inhibit the CoV replication in vitro (there are two different reports on that matter). So they may better than steroids in this case.

  24. George Stanchev says:

    Can someone comment on glycyrrhizin and alpha-monolaurin as supplemental compounds?

    1. Matthew Gassen says:

      Elaborate on your query. I have research experience with glycyrrhizin as an anti-inflammatory.

      1. George Stanchev says:

        Glycyrrhizin came up as a compound on the following list:

        with high number of references.

        Several articles describe it as having antiviral properties:
        Glycyrrhizin as antiviral agent against Hepatitis C Virus —

        Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus —

        Also, this: Small Molecules Blocking the Entry of Severe Acute Respiratory Syndrome Coronavirus into Host Cells —

        (the last one is about different compounds derived from traditional chinese medicine showing promise in stopping virus replication in vitro)

  25. Annonned says:

    Let’s say that one or more of these small molecules are found to be effective.
    Where and who is going to manufacture it?
    2009 there were shortages of Oseltamivir and other drugs since then more manufacturing has moved out of the US and Europe, the facilities closed and the people laid-off. More than 80% of the APIs are made in a limited number of facilities in China with questionable quality controls.

  26. JG says:

    Hi Derek – thanks for the analysis. Regarding this comment on remdesivir: “My personal opinion is that I like the chances of this drug more than anything else on this list, but it’s still unlikely to be a game-changer.” Can you say a little more about the reasoning behind that?

  27. A says:

    I’ve have been doing some research into characterising novel small molecule inhibitors of the lysosomal two pore channel (TPC) . As a family of drugs, these have shown effectiveness agasint Ebola but also coronoviruses such as MERS. Was wondering what people’s thoughts were on this field as I personally feel that it is often overlooked.

    1. GSK says:

      Never heard if it, are they similar to calcium channel blockers? They was used in Ebola with no benefit, and risk/benefit was not very good. Are they in use at the moment? Is there parent compound to compare it with?

      In any case it will take a really, really long time to get from lab to pharmacy, so it seems like a far shot for now,

      It seems innovation with small molecules is less active at the moment unfortunately as monoclonal antibodies and gene technology are better business models.

  28. Brian says:

    A, like I said, Amboxol is already OTC in most of the world besides the USA. If you can get it where you live, it’s safe and might help.

    1. A says:

      That’s quite interesting Brian, thank you for this. I wonder if Ambroxol has any effect on the TPC. This drug would be interesting to follow up on especially given its oral administration.

      1. brian says:

        It also works via Ca2+ in the lysosomes.

      2. Brian says:

        ambroxol is a frequently used mucolytic drug that triggers lysosomal secretion by mobilizing calcium from acidic calcium stores.[2] This effect does most likely not occur by a direct interaction between the drug and a lysosomal calcium channel, but indirectly by neutralizing the acidic pH within lysosomes. Calcium permeable ion channels in lysosomal membranes that may be activated by a luminal pH increase include two pore channels (TPCs), mucolipin TRP channels (TRPMLs) and purinergic receptors of the P2X channel type.

  29. Bryan Bishe says:

    One of the things I’m surprised I haven’t seen in other coverage of remdesivir is that it’s already been shown to be effective against coronaviruses. Feline Infectious Peritonitis (FIP) in cats is a generally fatal disease caused by a coronavirus. GS441-524 (remdesivir) showed a very strong response to curing cats of FIP. Pubmed link: [side note: I actually ended up ordering the chemical to treat my kitten that had contracted FIP. Normally cats die within ~5 weeks. My kitty has been alive over a year now, and it’s been 6 months since we finished the drug course]

    Obviously, not all coronaviruses are the same, but most of the coverage has noted how remdesivir was not effective against Ebola, rather than that it WAS effective against other mammalian coronaviruses. I’m surprised that the other study hasn’t been picked up on that much.

    1. Yarodur says:

      Absolutely! GS-441524 is the core of remdesivir. The difference is, and this is an important addition from Gilead, the presence of the phosphorus and the protective groups, that make remdesivir much more cell permeable and, even more importantly, much easier to get fully phosphorylated to be inserted into the viral RNA. So remdesivir is more advanced. However, if one used it in rodents, the results would likely to be the same between the drugs. Rodents have several hundred times stronger esterase activity in the blood/serum. Remedesivir would have been converted into GS-441524 before it gets into the cells. I don’t know if cats are closer to humans or rodents in that respect. I am just afraid, that humans would need larger doses of GS-441524 than remdesivir. On the bright side, GS-441524 could be taken orally, while remdesivir would probably be better off going though i.v.

    2. Marty Prince says:

      Hi there, Bryan. I’ve got a sick kitty. Would you be willing to share details on your administration, dosage, and chemical provider?

  30. Do you have an opinion of Galidesivir from Biocryst? It is being screened as a potential antiviral. Also, Biocryst lists it as a potential oral solution although they only completed 2 safety trials (I.M. and I.V.).

  31. Randall Sisk says:

    I wonder if any of the victims happened to br on an acyclovir, DNA polymerase inhibitor, to rule it out… or if anyone exposed but negative was on it … maybe. It’s common and available. I can’t find one statistic or lab on it however.

    1. This is all I’ve found on acyclovir. It states “Significant number of coronavirus patients with a history of taking valacyclovir (Valtrex) did not require hospitalization.”

      Identifying common pharmacotherapies associated with reduced COVID-19 morbidity using electronic health records

      1. Tuan A Elstrom says:

        i cant find that statement in your reference article?

  32. Mat says:

    What about glycyrrhizic acid(contained in licorice crude) against SARS-CoV-2?
    There are scientific data claims glycyrrhizic acid acts against RNA virus replication.
    Is there anyone know more?

  33. Joshua says:

    Okay, please, forgive me as it seems most readers and commenters here are above my IQ Level but, please don’t scoff me out of here.
    So I’ve been trying to research one simple thing and it has proven very difficult to find information on. My question is, has elderberry been tested against Covid 19?
    To my understanding Elderberry extract has been tested against 10 common influenza strains and proved to be very effective. Mostly tested in countries outside of the U.S due to our ridiculous money scheme of a pharmaceutical and pharmaceutical regulations industry as I understand.
    Has Elderberry or elderberry extracts been tested?

    If not, can anyone here better explain why not to a commoner like me?

    also, I don’t mind if you use these big ol chemical compound words I’m seeing tossed around but….if you’re using them at me..please, explain what they are so that a layman such as myself might better understand what the heck you just said. Thank you <3

  34. Save the World says:

    Hi folks, Is there a screening system for Covid-19 to check the activity of small molecule/peptide? OR We have screened using luciferase activity (?) targeting PLPro or 3CLpro. We could not find a screening system. If you share your views regarding the screening system it will be highly appreciated. Thank you,

    1. OEM says:

      You can find actual information about labs offering their services here:

    1. Klaus Witte says:

      PharmaMar’s Aplidin (plitidepsin) looks interesting. It inhibits eEF1A2, an elongation factor known to be involved in viral replication.

  35. Benjamin Stuhl says:

    Is anyone doing controlled studies of whether decongestants and/or expectorants change the progress and prognosis of COVID-19 cases? Since they modulate the physical properties (e.g. rheology and chemistry) of the mucus membranes, I would expect them to have *some* influence on how the CT-visible lung lesions behave. And even though they would have no impact on the SARS-CoV-2 virus, they might be useful or at least informative regarding COVID-19 the disease.

  36. steve says:

    I recently heard that Elderberry and Echinacea should not be taken because they can increase the cytokine storm, is this correct? Elderberry has always been used as an anti-viral

    1. Melinda says:

      I can’t speak to the Echinacea, but a study mentioned at
      says that “Non-cytotoxic, crude ethanol extracts of Rhodiola rosea roots, Nigella sativa seeds, and Sambucus nigra fruit were tested for anti-IBV activity, since these safe, widely used plant tissues contain polyphenol derivatives that inhibit other viruses.”
      This was a test against a coronavirus that causes respiratory illnesses in chickens. It was a lab test only, not on live subjects, and of the three plants mentioned, only elderberry had an effect.

      “These results demonstrate that S. nigra extract can inhibit IBV at an early point in infection, probably by rendering the virus non-infectious. They also suggest that future studies using S. nigra extract to treat or prevent IBV or other coronaviruses are warranted.”

      1. DrOcto says:

        recommended dose for the cell only experiment was 4 mg/mL. This corresponds to a dose of 320 g ethanolic extract 20 min prior to exposure in the average adult, probably intravenously (the ethanol alone would be lethal).

        Irresponsible to suggest that people begin taking these extracts as dietary supplements based on these results, it sounds a lot like snake-oil salesmanship. Their results MIGHT mean there is an active compound in the extract, but I’m doubtful at this point.

        1. c says:

          Absolutely. “Non-cytotoxic, crude ethanol extracts” is so obviously not the same as whole berries or syrup. Anything recommending Elderberry or echinacea or any other cytokine increasing remedies is probably a bad idea.

          1. G says:

            A 27 year old in vivo study, using a standardized elderberry extract at least showed promise in inhibiting the replication of influenza B. It is baffling to me that more rigorous studies haven’t followed.

    2. Bella says:

      Stephen Buhner (internationally renowned clinical herbalist has debunked this re elderberry). He also advises that the elderberry leaf would be more powerful.

  37. Yarodur says:

    What about emetine and the ipecac syrup? There are quite a number of papers about its inhibitory effect of emetine on CoV replication. It is a chemical widely used in research to block the protein synthesis in cells, so the idea is to find the low doses when viral protein synthesis is preferentially affected. I am most probably wrong, but my estimate is that one needs only about 1:10 of the usual emetic dose. It seems to work at sub-micromolar level, according to some papers, or micromolar at worst. It is not terribly safe drug, but it is still sort of clinically-approved, so there may be a chance of re-purposing.

  38. Heba Elseidy says:

    what about tetracycline ?? have you tried any tetracycline with patient tested positive Corona virus?
    The binding of the tetracyclines to dsRNA may also explain the
    mechanism of their action against viruses. Since the viruses
    against which they are known to be effective by inhibiting/suppressing viral replication are RNA viruses (14), for example, WNV
    (2), JEV (70), and HIV (3), the tetracyclines may bind to these
    viral particles or products to activate or inactivate some other
    molecular pathways involved in the viral response (76–78). Most
    viruses produce dsRNA structures during replication. In flaviviruses (WNV and JEV), dsRNAs are often produced by RNA-dependent RNA polymerases during viral replication. In retroviruses (e.g., HIV), dsRNA is produced by the base-pairing of
    primer tRNA with the genomic RNA, forming a substrate for the
    reverse transcriptase (79). Also, replication of these viruses, like
    most RNA viruses, takes place in the cytoplasm of host eukaryotic
    cells, where ionic conditions (particularly Mg2 concentrations)
    are favorable for doxycycline/minocycline binding. On the contrary, replication of most DNA viruses takes place in the host eukaryotic cell’s nucleus. In addition, a number of host defense
    mechanisms and innate immune responses are activated by
    dsRNA intermediates of viral replication, such as the RNA interference pathway and Toll-like receptor 3 (TLR3) activation of
    NF-B and interferon production (78). Some of these immune
    responses are also indicated in the anti-inflammatory activities of
    the tetracyclines. Some viruses, particularly HIV, are known to
    successfully evade these host immune responses. It is possible that
    minocycline suppresses both viral replication and activation of the
    inflammatory and cellular responses to these viral infections via
    an effect on dsRNAs (14). Hence, the antiapoptotic, anti-inflammatory, and antiviral activities of minocycline that have been observed in viral infections (2, 13, 14, 68–70) may also be mediated
    via interactions with dsRNAs. Further investigations in line with
    the dsRNA binding perspectives are, therefore, quite imperative

    1. Yarodur says:

      You could extend your search to pradimicin. PrA is a small molecule with lectin-like properties. Lectins are proteins able to bind sugars. PrA binds mannose. Coronaviruses are heavily glycosylated, with mannose being the key constituent of those corona spikes, which virus uses to bind the cells. Thus, blocking mannose is expected to inhibit the viral transport into the cells.

      1. MD-PHD says:

        Lectin/mannose are often part of of immunogenic glycoproteins I would be very careful adding that to the mix as part of the problem is over-reaction of the immunesystem.

  39. An Old Chemist says:

    The world’s fastest supercomputer identified chemicals that could stop coronavirus from spreading, a crucial step toward a vaccine

  40. celticgirl says:

    What about Osha root ? Do you think it would help in any way ?

  41. Bill says:

    One of the best articles I’ve come across yet.. little background. I just finished an around the world trip on the 15 of March landing back here in Vancouver. I passed through New York, London around Feb 11-13 ..then Dublin.. layover Doha and One Month in Thailand. I may have just missed the transmission points but even i find that hard to believe. Reporting on anything in Thailand is to be considered suspect at best..lots of sneezing coughing etc going on..but with the pollution levels allergies you name it i just wrote it off to that. Life is relatively cheap wearing masks wasn’t something most people cared for. I think the heat obviously does not offer an optimal obv cold countries appear most at risk..but then Spain and Italy.. this is still evolving..and it is still winter like even in those countries. In Thailand i had planned to travel.. decided against and stayed in one spot avoiding known covid areas.. wanted to go Myanmar but thought who knows with borders etc as evolved.. i had started taking Malarone tablets in case i did go.. my question is ..could i have possibly immunized myself to some degree? I dont know if i believe that because i had only taken around 4 tablets.. one a day then stopped. But I’m wondering is low dosing an immunizing possibility. This is why I’m a firm believer that anti malarials need to be distributed aside of side effects. To every man woman and child if this curve is to be flattened as much as possible. A 10 day dosing would be my guess… but it doesn’t necessarily have to be high for the uninflected..just enough to keep the virus from getting a foothold. Papers i have read.. mention 3 things that stand out.. halting the replication capabilities in red blood cells or basically making it toxic for the virus, PH levels also intrigues me as i seem to remember this being something in the past people were using to combat something. This last one is a big one and you mention in your article the effects on glucose or insulin levels..something like that. Excuse me but I’m not a scientist.. i did see that number IB something out there… these are three main areas of attack aside of all the rest. The PH alteration could possibly be one of the cheapest and easiest if it worked. Glucose levels seem too be gasoline for everything to go wrong in health and i could easily see altering or balancing sugar levels in the body as one method of also reducing succeptibility. So I drank lots of beer in up to a pack a day of Marlborough’s so arriving home I’ve had a smokers hack as my lungs are clearing. I reduced cigs to a few a day and haven’t had one in the last day and a half as i realize this leaves me wide open. Ive continued taking the malarone when finding out it has antipneumonocystic capabilities..because going from 31c temps with mass humidity to 10c and relatively no humidity is its own shock on the system..its a balancing act. The worst possible side effect of mass dosing is creating resistance whereas then people could be left wide open.. but having multiple options like Chloroquine.. then remdesivir etc could be a balancing act. I think the side effects of Covid being death are far worse than some side effects from Malarials..and if someone is allergic etc..then something else could be considered. I dont know about you but i dont want to see a million or two people dying unnecessarily when there is an option… why not start large scale tests on low dose medium and high dose.. and i bet if you offered the population the option to have a 10 day dose they would jump at it. Just saying. It’s all intriguing.. even the ramping up and mass long could things be done with gmo brewers yeast etc. We’ve had years and things haven’t improved in science..everyone still wants to do studies.. test things..navel gaze. The science community needs to get its ass in gear more than ever..this wont be the last time we see something like this..and if it mutates to out

  42. LDAF says:


    This may be of interest:

    A trial is starting to investigate the use of colchicine as a way to dampen the immune response to the virus…

    1. milkshake says:

      colchicine is an ugly drug, has almost no therapeutic window. It would make a better sense to try antifolates like metothrexate, especially since there is a rescue antidote

  43. Jacob says:

    What about Black Cumin Seed ? Does anyone have the scientific reason why corona virus get destroyed when Black seeds are used ? In Internet there is no search for this at first sight… And people are using it and getting positive results …

  44. Matthew hayman says:

    Do you have an opinion of Galidesivir from Biocryst? It is being screened as a potential antiviral. Also, Biocryst lists it as a potential oral solution although they only completed 2 safety trials (I.M. and I.V.).

  45. Samares C Biswas says:

    I was going through some of the literature on the antiviral effect of tea, specifically green tea. It has been reported that tea (green tea) is effective on Influenza, Zika, Chikungunya, Adenivirus.

    I was wondering, if same can be use for boosting immunity in the current situation.

  46. Toni says:

    Niclosamide looks interesting. Recently also discussed as a repurposed drug for oncological applications. (reminds me of Joe Tippens deworming/fenbendazole treatment 8 his lung carcinoma)

  47. Ali Ml says:

    I wonder whether AMPK activation could be useful to treat Covid-19 & reduce SARSCoV2 replication in airway epithelium?

  48. Dawn says:

    My family was already sick with what seemed to be the exact symptoms of COVID-19 back in January this year. One member almost went to the hospital over breathing issues. It was odd that I did not catch it since I’m more susceptible to viruses etc. I’m on DOXYCYCLINE and I swear that had to be the reason I didn’t catch what they had… They were coughing for nearly a month. It was basic fatigue, fever at the onset and then a little bit of cold symptoms with a nagging dry cough that could get bad at times.

    1. DB says:

      Thanks very interesting dawn. I have a theory doxycycline may be effective prophylaxis.

    2. Rich J says:

      Dawn, What dosage of doxycycline? The 50mg low dose for rosacea? Or 100 to 200 mg antibiotic dosage? Doxy is an antiflammatory and metalloproteinase inhibitor at low dose (20-50mg).

    3. drsnowboard says:

      And were you in contact with someone from Wuhan? There are a number of respiratory viruses.

  49. Adriano Cliff says:

    Can someone with chemistry/pharmacology knowledge explain why remdesivir is not orally bioavaiable? Similar drugs like sofosbuvir and tenofovir alafenamide are oral.

  50. Robert Hurwitz says:
    …perhaps it is not the absorbtion but toxicity of this C-Nucleotide. (the analogue without a cyanogroup is even more cytotoxic)
    “Moreover, oral delivery in patients acutely infected with EBOV that are demonstrating symptoms of the disease may not be ideal because gastrointestinal symptoms may limit the dose that is effectively absorbed”

  51. Khorsed Alam says:

    Dear Sir ,
    I am cordially requesting you to tell me or write me please about the Acid and base reagent of this Covid-19 virus .
    what is the main characteristics of this virus that can not matches with other viruses .

    How it is made from and how we can destruct this virus , i need some idea about that .

    best regards
    Khorsed Alam
    BSc. Textile Engineer

  52. PJ Murdock says:

    Iodine kills viruses, so why isn’t nascent iodine or Lugol’s being used against Covid-19? There are many medical papers as to efficacy and prior universal use.
    Thank you.

    1. Kate says:

      I’m started taking Lugol’s iodine in January to boost my immune system and protect from viruses. Since Covid 19 deaths are from inflammation and iodine reduces inflammation it seems like a good preventative strategy. Since there’s no money in it, I don’t expect Doctors who are but agents of Big Pharm to recommend natural products.

      1. drsnowboard says:

        Pray tell the research that proves oral iodine solution is anti-inflammatory. And please reveal your source of the free lugols as obviously there’s no money in it…

        1. Jim Watson says:

          “There’s no money in it” would refer to the fact that pharmaceutical companies can’t patent Iodine.

        2. Jim Watson says:

          there’s no money in it would refer to the fact that iodine can’t be patented by pharmaceutical companies. Regarding anti-inflammatory properties, I too would like to see a reference

  53. Ebola virus disease (EVD) was first documented 40 years ago during an outbreak of infectious hemorrhagic fever in Northern Zaire (current Democratic Republic of Congo). More than 20 intermittent outbreaks have occurred since then, but the most recent outbreak in West Africa spanning 2013–2016 has been the largest recorded in history and presented an international public health emergency.

  54. UK Observer says:

    “chloroquine / hydroxychloroquine, azithromycin, and lopinavir-ritonavir have a variety of adverse effects, including QT prolongation, torsades de pointes, hepatitis, acute pancreatitis, neutropenia, and anaphylaxis.

    Considering that most patients who have died from COVID-19 were elderly and had cardiovascular comorbidities and that affected patients frequently have cardiac arrhythmias,4,5 chloroquine/hydroxychloroquine, azithromycin, and lopinavir-ritonavir could potentially increase the risk of cardiac death

    The use of intravenous steroids has been associated with delayed coronavirus clearance in both blood and lungs with MERS-CoV6 and SARS-CoV,7 and steroids were associated with significantly increased risk of mortality and secondary infections in patients with influenza.8

    Furthermore, even low-dose steroids have shown harm in patients with sepsis, and IL-6 inhibitors may cause even more profound immunosuppression than steroids, increasing the risk of sepsis, bacterial pneumonia, gastrointestinal perforation, and hepatotoxicity.9,10 Yet, despite substantial evidence of potential harm, steroids and IL-6 inhibitors are now being given to patients with COVID-19 in several countries.”

    1. James Broadbent says:

      Hinokitiol on the other hand has no side effects at effective concentrations and is approved as a food additive in Japan. Worth having a look at since it is also a Zinc Ionophore and posseses antiviral and anti bacterial properties of it’s own.

  55. Rich J says:

    Important correction: Anti hypertensives lisinopril and losartan INDUCE ACE2! Per Tony Fauci, 75% deaths in Italy have hypertension. How can it be that controlled hypertension is the major underlying condition associated with death in Italy which has excellent medical system? The drugs are highly suspect. Dr. Fauci urges hypertensives to talk to their cardiologist.

    Here’s the original hypothesis:

    1. Rich J says:

      It turns out that anti-hypertensives May be beneficial in treating Covid19. That was observed in previous epidemic and there is an ongoing trial now. More receptors does not necessarily increase infectivity, which is actually the case for HIV. Don’t change meds, and talk to your doctor!

  56. HA Lurker says:

    Any thoughts on the Aviptadil trial? Seems to be a small peptide.

    Was asked for my opinion (as a first-year biochem student…) by an elderly relative, and I can’t find anything about it.

    (Trial details can be found at NCT04311697)

    1. Derek Lowe says:

      Vasodilator, and there appear to be several people thinking along those lines. Sildenafil is going into a trial as well – this would be to protect against lung damage, not as an antiviral per se.

      1. HA Lurker says:


        (The old man (obviously self-isolating) cheers himself up by latching on to any positive medical news he finds, and I try to debunk the obviously bogus ones so he doesn’t get worked up by something doomed from the start – anyone else here providing this ‘service’?)

  57. Rich says:

    New study from Paris: “No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection

  58. Zafer Zeybek says:

    Dear Researchers,
    Can glycoproteins in the outer structure of the coronavirus be inactivated by binding with polyhydroxyphenols, such as gallic acid, by complexation? Can not a drug for this purpose be developed from products containing tannins (sumac, acorn, etc.)? I am curious about your thoughts.

  59. Carolyn cox says:

    Any data on patients testing positive for covid-19 having previously completed two doses of Shingrix vaccine?

  60. David Proteus says:

    Maybe this was already discussed and I missed it. Quercetin has been proposed as a COVID-19 treatment. There was prior evidence that it could protect mice from Ebola and Zika virus. Also there is lab evidence of efficacy against SARS. And one small clinical trial demonstrated a general anti respiratory viral protective effect . An animal study showed a protective effect against H1N1. The Montreal Clinical Research Institute is said to be investigating it in COVID-19. It reportedly works through various modes of action, including inhibition of TNF-alpha and possibly through ACE2 modulation.

  61. Janvi says:

    Rhodiola is popular for immune benefits,and whether could be recommended as supplement,???

  62. Yarodur says:

    Ulinastatin ( , a serine protease inhibitor (so must be good for 3CL and furin) and anti-inflammatory protein used is approved in 4 countries (Japan, S. Korea, China, and India) for i.v. use in quite a few diseases, including sepsis and acute lung injuries, if I am not mistaken. May be a good alternative to camostat and nafamostat (also Japanese drugs but not as widely approved).

  63. Martha Whitehill says:

    Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV2-Priming Protease TMPRSS2

    ***suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency”*** = Rx: ****Vorinostat***is also a HDAC inhibitor – mitochondrial lysine acetylation involved with Sirt 3 acting as a deacetylase.

    Alpha-1 antitrypsin (A1AT) is an acute-phase protein, and is best known as an inhibitor of the serine proteases, specifically, neutrophil elastase, proteinase 3, and cathepsin G. (=3)


    (Histone deacetylases (HDACs), also known as lysine deacetylases)

    Interestingly, TUDCA dependent inhibition of class I and II HDAC enzymes restored the expression GLUT4, resulting in improvement of insulin sensitivity and glucose tolerance [189]. Moreover, TUDCA has been found to modify the expression of sirtuins, which are NAD-dependent deacetylases responsible for removing acetyl groups from many histone and non-histone proteins

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