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Omeprazole As An Additive For Coronavirus Therapy

One of the notable things about the current pandemic is the way that all our modern biology and analytical techniques are on display. Molecular biology, structural biology, bioinformatics, technologies like cryo-EM structure determination, fast sequencing, protein interaction screening and more – this is a real-time look at how basic biomedical research gets done. I’ve been reading a new preprint that starts off with protein sequence analysis and ends up with an actionable clinical recommendation (skip to the end for that one!), and I think it’s a good illustration.

This team from Germany and the UK has been analyzing the new pathogen with a technique they’d already developed to look at differentially conserved amino acids among related strains. Comparing the current SARS-CoV-2 and the earlier SARS-CoV, they find that most of the amino acid changes are conservative (one hydrophobic residue swapped for another), with some polar/nonpolar swaps and very few instances of swapping charged residues. That’s about what you’d expect, of course, but the question is whether any of these are functionally relevant. A closer look shows that these differentially conserved positions are found much more in the notorious “spike” protein region than (say) in the envelope proteins, and that overall 92% of these changes are on protein surfaces rather than buried residues, which makes you think that they are indeed important.

It’s already been noted that several residues involved with the spike (S) protein’s interaction with the human ACE2 protein vary between the older SARS virus and the new one. This group went on to look at various human cell lines and their susceptibility to viral infection, and found that while the presence of the ACE2 protein in general is important, there are more things at work. For example, 293 cells (kidney-derived) don’t express ACE2 at all, and had been shown during earlier work on SARS to be resistant to infection. The new coronavirus doesn’t infect them either – but if you engineer the cells to express ACE2, original SARS will then infect them, but the new virus doesn’t do so nearly as well. Across several other cell lines, there is no good correlation between the amount of ACE2 present (as long as it’s there in some amount) and the ability of SARS-CoV2 to infect them, so it’s not just a simple “the more ACE2 the worse” situation. We don’t know what the other factors are, but there clearly are more than just ACE2 levels.

They also looked at transmembrane serine protease 2 (TMPRSS2), another human enzyme that is hijacked to allow viral entry (and which is a target of the serine protease inhibitor camostat, a drug that many readers will have heard of by now and which is in clinical trials against the current virus). As with ACE2, susceptibility to SARS-CoV2 didn’t correlate with TMPRSS2 levels, either, though – more evidence that things aren’t as simple as you might hope. The paper goes on to look at camostat itself and another similar protease inhibitor, nafamostat, which is also approved in Japan for pancreatitis. Both drugs are more active against SARS-CoV2 infection in cell culture than they are against the first SARS virus, and nafamosat is more active than camostat. Unfortunately, the concentrations that are needed in the cell assay (0.5 and 1.2 micromolar respectively) are still above what these drugs appear to achieve in vivo (reported plasma concentrations of 0.2 micromolar), so we’ll have to see from the human trial data if that’s enough to show efficacy. It’s not wildly far off, particularly for nafamostat, but you’d still rather have it the other way around, for sure.

But there’s some possible good news as well. The team also looked at the serine protease inhibitor aprotinin, a small protein inhibitor of serine proteases that has had an up-and-down history in human therapy and has been looked at as an antiviral as well (via its TMPRSS2 inhibition). As Trasylol, it was used to slow down bleeding during surgical procedures (by inhibiting several proteases in the fibrinolysis pathway), but as with all drugs that either enhance or reduce blood clotting, you’re walking a fine line between benefit and trouble. Apronitin was temporarily taken off the market in 2007 because of possible association with clotting events, but this suspension was lifted by the EMA in 2012 after further review of the data. In this work, though, apronitin was not only more potent in the cell assays, it displayed much stronger effects on the formation of double-stranded RNA (a marker of viral infection), and did so at levels below the known blood levels on human administration. It’s more effective on the new coronavirus than it is on SARS, which seems to be partly explained by the sequence differences noted above. The authors say:

Since aprotinin interferes with SARS-CoV-2 in therapeutic concentrations and displays more pronounced direct antiviral effects than camostat and nafamostat, it seems to have a greater potential for the treatment of SARS-CoV-2-infected individuals based on our data.

You’d want to be careful with this drug because of its past history, but the authors note that there is actually an aerosol formulation of apronitin that’s been approved in Russia, so that mode of administration looks feasible and might have less systematic risk.

The paper goes on to look at another approved drug that I haven’t seen getting as much attention: omeprazole, the well-known proton pump inhibitor for acid reflux. It has been reported as having some antiviral activity in the past, possibly by increasing the pH in lysosomal compartments. In their assays, it did interfere with viral infection, but at levels too high for realistic human dosing. But here’s the interesting part: they found that simultaneous treatment with omeprazole (at human therapeutic concentrations) increased the activity of apronitin by 2.7 fold and increased the activity of remdesivir by 10-fold. That seems like a very useful observation! As far as I can see, the paper did not check for an interaction of omeprazole and camostat/nafamostat, which would be interesting to know as well. The same group had noted in 2019 that the drug increased the activity of acyclovir against the herpes virus.

So while we’re still figuring out if remdesivir has efficacy by itself, there’s an opportunity to administer a widely used, well-tolerated drug to give it a better chance. And both the beneficial interaction of omeprazole with apronitin and the earlier acyclovir/herpes result suggests that this could be a more general effect with many other drug candidates, which seems well worth investigating.

31 comments on “Omeprazole As An Additive For Coronavirus Therapy”

  1. Mark says:

    Omeprazole is a good example of the vagaries of medication/doctoring. I have GERD and used omeprazole for about four years. Last year my primary care doctor convinced me to switch to famotidine because there was some evidence that omeprazole was a risk factor for dementia. This year famotidine was pulled due to contamination with carcinogens. I was trying to get by on antacids and having a fair amount of discomfort; it got so bad I almost gave up drinking. Luckily, I found a recent meta-analysis of omeprazole that shows no increased dementia risk.
    Ars longa, vita brevis est.

    1. PV=nRT says:

      Ranitidine (zantac) is the one that had a carcinogenic contaminant, not famotidine, that I can see. PPIs do increase one’s risk of gastric cancer, unfortunately.

      1. MagickChicken says:

        Do PPIs actually increase risk of gastric cancer, or do patients that take PPIs have a higher incidence of gastric cancer, possibly because of the lowered pH and increased gastric reflux into the esophagus?

        1. Gabriela Lellis says:

          As my gastroenterologist, either risk cancer from the lesions in the esophagus, or risk cancer from taking Omeprazole. I prefer the more comfortable way of living without GERD symptoms.

          1. Mik says:

            I think that statement is too broad. There is doubt that the link exists, at least in that way. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415482/

      2. Mark says:

        They yanked all H2 blockers at the pharmacies around me.
        My point was that the final word on a pharmaceutical is not written for a long time even for drugs approved years ago.

        1. loupgarous says:

          The gastroenterologist in my cancer care team (the guy who found and removed cancers during an endoscopy) put me on Protonix for stomach ulcers. I’d say there’s a risk/benefit ratio at work there, I’d had a fair bit of my stomach removed earlier for infitration by neuroendocrine cancer, but that’s not the same thing as stomach cancer, histologically.

      3. Nathan says:

        Unfortunately I can’t Find it In the Uk is been taking of the market or change to a different name (Famotiden/pepcid)

    2. Jim Feerick says:

      It was all manufactured formulations of ranitidine that was pulled, not famotidine.

  2. Cb says:

    A question put forward earlier in this blog: “why are we so afraid to give non selective irreversible Cys protease binders for 1 or 2 weeks p.o. in the mid of the pandemic if we use them as existing drugs already and are apparently safe enough: acetaminophen/paracetamol (NAPQI metabolite), omeprazole, dimethyl-fumarate, disulfiram”

    Omeprazole and many analogues such as Lansoprazole give active rearranged sulfenamide which act also as non-specific irreversible (disulphide formation) Cys protease inhibitor. I found such drugs not only in screening campaigns of Cys-proteases (the molecules apparently also rearrange in screening samples), but also have shown to inhibit Cys protease such as Legumain and CatB: https://doi.org/10.1111/bcpt.13230 . So no AI or other high-tech needed to suggest these drugs as potential inhibitors of the SARS-Cov2 Cys protease (coronavirus Mpro enzyme)

    1. Derek Lowe says:

      I would be very surprised if omeprazole’s efficacy (if it has efficacy in human subjects) were through cysteine protease inhibitor.

      1. Cb says:

        Yeh Derek, agreed, I would also be very much surprised if omeprazole or any other existing drug could be repurposed as anti-SARS-Cov2 drug. Perhaps some existing antiviral active on RNA viruses has some chance if given early in the disease, but if you administer in the critical phase (e.g. remdesivir) it would be very difficult to win the uphill battle (as seen e.g. with Tamiflu: first 24 hours works very good, but hardly if you really suffer from the flu; same for acyclovir and cold sore). Making effective anti-HepC drugs took ages albeit that they had the advantage that even non drug-like big molecules could be used accumulating in the liver: fortunately the target organ for HepC virus.

        On the other hand in the recent paper: https://doi.org/10.1111/bcpt.13230 they show that omeprazole PPI class molecule (i.e. the rearranged sulfenamide) inhibits cys proteases . It is just remarkable that it has not been tested on the SARS-Cov2 cys protease (same holds true for other existing drugs: dimethyl-fumarate and acetaminophen metabolite NAPQI), in particular regarding the reactive molecules put forward in the recent Nature paper you presented a few days ago.

        Finally, I wish to mention that I see several publications regarding “The Small Intestine, an Underestimated Site of SARS-CoV-2 Infection”; presumably the small intestine may get exposure of the reactive sulfenamide from PPIs.

      2. Cb says:

        Actually, I feel repurposing drugs to suppress the cytokine storm and ARDS by Moab’s (e.g. IL6) and small molecules (anti btk) may be more successful for very ill patient than anti-virals. It is interesting to see that a nice covalent inhibitor of btk from my labs, which was ‘forbidden’ by big Pharma X (‘covalent inhibitors are not allowed here’) and bought, developed and marketed by Pharma Y is now tested in hospitalized-Covid 19 patients. The covalent btk inhibitor mentioned is quite selective, but perhaps very unselective and easily available omeprazole, dimethyl-fumarate and NAPQI inhibits covalently Cov-Cys proteases some endogenous btk etc etc and also works …….but of course I am looking forward to the results with the ‘forbidden’ selective covalent btk inhibitor

  3. Barry says:

    The Pummerer rearrangement of Omeprazole creates a pretty hot electrophile that can bind irreversibly to many structures, not only to free cysteines. Its chemistry is driven by the acid-driven rearrangement, not by the incoming nucleophile.
    A viral cysteine protease would only be hit if it were presented along with an acid source.

    1. Cb says:

      The rearrangement to the reactive sulfenamide (cysteine reacts with reactive S-N bond of this intermediate) occurs rapidly under acidic conditions in the stomach and in lysosomes. The stability at PH 7.5 rt is better: t1/2 ~7days, so take care of your samples in solution.

    2. Subhash says:

      Pardon intrusion but Would Ascorbic acid (VitaminC) work as that acidic compliment to Omeprezole to hit the Viral Cysteine protease enzyme, just my conjecture

  4. Combo PK says:

    Indeed an interesting observation to increase antiviral activity of Remdesivir by combination with Omeprazole. To properly test this hypothesis in human, one would need to consider the different PK profiles and tissue concentrations. Likely both compounds need to be present at the same time in the right tissue and ratio to one another – can be tricky!

    1. RDR says:

      If we considering that omeprazole tends to accumulate in gastric cells due to its protonation state at low pH, we might never see the synergistic effect in vivo.

  5. Madeleine Strickland says:

    Proton pump inhibitors have been shown to inhibit multiple viruses that pass through membranes using the ESCRT complexes:
    https://www.nature.com/articles/s41598-020-60544-y
    The mechanism is through covalent binding to the UEV domain of Tsg101 (part of the ESCRT-I complex).
    https://www.nature.com/articles/s41467-017-01426-2
    It’s possible SARS-CoV2 uses this mechanism but we don’t know yet. It would explain the results shown here.

  6. Apparently, low pH is a “cue” for most viruses to activate their machinery inside the cell. Here’s the story of how the relationship was discovered: https://www.nature.com/articles/ncb2678

  7. Kathy says:

    Is there updated information on the mechanism of “sartan” medications or other factors contributing to blood pressure patients such high risk of death from the virus? Anything patients can do (besides hide) to mitigate risk?

    1. Derek Lowe says:

      The latest is that hypertension patients on these drugs (either the “sartan” ARBs or the ACE inhibitors) actually do *better* during the viral infection than those who are taking other therapies. It looks like the lung damage is partly mediated by angiotensin effects, so reducing those can help.

  8. cynical1 says:

    “The new coronavirus doesn’t infect them either – but if you engineer the cells to express ACE2, original SARS will then infect them, but the new virus doesn’t do so nearly as well.”

    “Across several other cell lines, there is no good correlation between the amount of ACE2 present (as long as it’s there in some amount) and the ability of SARS-CoV2 to infect them, so it’s not just a simple “the more ACE2 the worse” situation. We don’t know what the other factors are, but there clearly are more than just ACE2 levels.”

    This was a study investigating the growth of the virus in various colorectal cell lines and you want me to believe that the added effect of a PPI (omeprazole) means what exactly to an irrelevant cell line with no translation to any hope of in vivo anything and should matter for what reason? Pray tell why did they not look at the differential effects of esomeprazole versus omeprazole??? The study seems to show that colorectal cell lines are probably not useful in any sense for studying infectivity with coronaviruses other than you can engineer them to harbor the virus…….sometimes…..maybe….if you overexpress ACE2 …….but not always. They basically mean nothing and should be interpreted that way. That is what the study showed.

  9. David says:

    If there’s really a synergistic effect between omeprazole and, say, remdesivir, it likely will initially show up as noise in the remdesivir trials. Lots of patients are put on PPI drugs at time of intubation. Sorting out a signal from that will be tricky. Then, running a human trial designed to show an interaction will be challenging.

  10. Simon Auclair the Great and Terrible says:

    Anyone have an opinion or knowledge of this? It seems to go beyond the “no tests therefore no virus” we’ve seen before.

    https://asiatimes.com/2020/04/balis-mysterious-immunity-to-covid-19/

  11. Giannis Zaxarioudakis says:

    The omeprazole news are very good. If they increase the effectiveness of remdesivir that means that we can lower the remdesivir dose. Unfortunately remdesivir is a very hard molecule to make and gilead will only be able to create enough drug for 500K people till October. If omeprazole/esomeprazole (which is readily available) are effective at increasing the efficiency of remdesivir 10 times then potentially 5 million people could take the drug till October!

    1. loupgarous says:

      “If omeprazole/esomeprazole (which is readily available) are effective at increasing the efficiency of remdesivir 10 times then potentially 5 million people could take the drug till October!”

      Clinical studies still haven’t established a useful degree of efficacy of remdesivir in Covid 19, much less a useful (and safe) dosage regimen for SARS_CoV2 infection.

      There isn’t evidence showing (using omeprazole as a synergist) that you can cut the present estimated minimum dose of remdesivir down by a factor of 10 and synergistic activity will make up the difference. Any increase in effectiveness due to concomitant dosage with omeprazole may require a minimum dosage of remidesivir to be given first – so you might not do anything useful with 1/10th the current dosage of remdesivir, even if omeprazole’s given with it.

      Another randomized controlled study at least would be needed to show that effect working in humans (the 10-fold improvement is only being seen in cell assays at present).

  12. Britton says:

    Does taking Omeprazole minimize the effectiveness of other medications one is taking? I cannot get a straight answer on this from my primary, dermatologist etc… If so, could I / Should i stagger when i take it? (Taking Losartan and Doxycycline)
    thank you!

  13. Brandon Block says:

    One question — does using any acid blocker on a COVID19 patient increase the likelihood of the virus entering and affecting the gut?

    1. Richard Simpson says:

      It might be an over simplication and I am not a microbiologist, but there is some suggestion that the use for example of pantoprazole reduces stomach acid which would normally kill covid-19 entering the stomach from the saliva (unpleasant but gaining strength) of fecal/oral transmission of the disease. So with great expression of AEC2 in the gut lack of acid offers a more vulnerable target. Logically makes some sense to me but these are early times.
      Here is a non-medical reference article
      https://time.com/5837591/unusual-symptoms-of-coronavirus

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