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Drug Assays

Zika Cures? Not Quite Yet

There’s a paper out in Nature that’s gotten a lot of attention, because it’s directed towards therapies against Zika virus infection. The authors (a multi-center team) screening a library of existing drugs, known active pharmacological agents and tools, clinical candidates, etc. in a caspase-3 assay, since they’d recently found that zika infection in the CNS activates the caspase system.

Not surprisingly, they turned up emricasan, a known caspase inhibitor that’s been in the clinic in trials against chronic liver disease. Niclosamide was another hit, an old antihelminthic compound that’s still in use, although its side effect profile limits how often it’s used compared to alternatives. A third compound, PHA-690509, also showed efficacy – it’s a CDK inhibitor that’s been as far as Phase I, from what I can see. A number of other CDK-active compounds were also hits, which does point to it being involved in the infection process.

I think that the main value of these screens is often to point out mechanistic details like this – the drugs involved are being used as chemical probes, since their actions in cell assays and in vivo are fairly well worked out. (It’s for sure, though, that not every marketed drug is suitable for use as a probe – some of them hit a whole range of targets simultaneously). If an actual drug on the market hits (as niclosamide did here), that would speed up the possibility for its use against Zika infection, but it’s still something that would have to be taken through animal efficacy studies and human trials. In vitro screens are where most drugs get their start, for sure, but an awful lot (and I mean literally awful) never get much further.

This is all to say that the headlines generated by this work in the press (“Known drugs could cure Zika”) are way premature. The paper itself makes sure to say that further animal studies would be needed before you could even start talking about a human therapy, but that doesn’t make for such a great headline. It’s certainly a jump-start compared to a completely new compound, but it’s a lot further away than people might think. It takes time to set up a trial, to get the patients, and to figure out what happened once the dosing has finished, and none of this fits very well into the sort of dramatic narrative that the newspaper business would like.

22 comments on “Zika Cures? Not Quite Yet”

  1. Barry says:

    To show that Caspase-3 expression goes up in response to Zika infection is a long way from showing that blocking Caspase-3 function could block Zika infection

  2. MouseTrap says:

    Are there any animal models available for efficacy against Zika virus?

  3. Anon says:

    There was also a quite premature paper on aducanumab in Nature. I mean, everything about AD is premature until PhIII results, but media was so impressed: “Breakthrough cures Alzheimer!!!”

    1. Mark Thorson says:

      I’m not a supporter of the Amyloid Cascade Hypothesis 2.0, but there is a very good recent review by its main proponent (Selkoe, of course). Although I view some of his statements with deep skepticism, he does make some good points that any critic of the hypothesis should be prepared to answer. The argument from the genetic data is a strong one — if there was another cause, why do we not see mutations which affect that other cause appearing in early-onset AD?

      http://embomolmed.embopress.org/content/embomm/early/2016/03/29/emmm.201606210.full.pdf

  4. Sean Fearsalach says:

    An obvious problem is that Zika is not a very serious disease except in pregnant women — and developing a drug specifically to be given to pregnant women is more difficult. Teratogenicity of antivirals can be a real problem.

  5. MachN says:

    Give the infected Minocycline, a known caspase 3 inhibitor and cheap as sea salt. Unfortunately no one will make a dime off it and its pleiotropic mechanism of action scares Pharma.

    1. a says:

      It should scare you too. What if it causes birth defects in 1 / 10 000 of the grandchildren of women dosed wtih it? You’d never catch that until phase 4.

      1. Mach says:

        Birth defects in grandchildren? You would never catch that at all. Are you suggesting an epigenetic mechanism of action of Minocycline and do you even know what you are talking about?

        1. Wile E. Coyote, Genius says:

          Try diethylstilbesterol for something that produces an effect in grandchildren and skips the intervening generation. Can happen, can be caught. That is why they now do multigenerational tox studies for drugs intended for pregnant women.

        2. RM says:

          You don’t necessarily need to invoke epigenetic mechanisms when you realize you can replace “birth defects in … grandchildren of [pregnant] women dosed with it” with “life-long abnormalities in gamete production for people who were exposed as fetuses” and maintain the same meaning.

      2. sort_of_knowledgable says:

        For a treatment for acne, a 1 in 10,000 chance of a birth defect is worrisome. For a treatment for Zika which seems to give a 1 in 10 chance of a birth defect that’s a minor defect.

    2. nope says:

      Unfortunately, you can’t give tetracylines to pregnant women:

      Minocycline has been assigned to pregnancy category D by the Food and Drugs Administration (FDA). This means that there is clinical data about teratogenic effect on people and animals. However, in some serious or life-threatening conditions the expected benefit can outweigh the potential risks for the fetus.

    3. nope says:

      Unfortunately, you can’t give tetracylines to pregnant women:

      Minocycline has been assigned to pregnancy category D by the Food and Drugs Administration (FDA). This means that there is clinical data about teratogenic effect on people and animals. However, in some serious or life-threatening conditions the expected benefit can outweigh the potential risks for the fetus.

      from http://www.drugsdb.com/rx/minocycline/minocycline-during-pregnancy-breastfeeding/

  6. Flavi of the Month says:

    Since Zika is a flavivirus (like HCV) and since there’s a small mountain of idle project compounds leftover from the HCV pipelines, it would be nice if industry and government could cooperate in identifying potential low-hanging fruit (legacy “HCV” direct-acting antiviral compounds that could be repurposed for Zika). A quick look suggests there’s fairly low homology between Zika and HCV proteins, so it’s unlikely that optimized DAA HCV clinical assets would be efficacious towards Zika. On the other hand, weak HCV inhibitors could show significant Zika potency – i.e. you’d probably need to screen all HCV-associated project compounds, looking for Zika inhibitors. In principle, Zika replicon assays should be straightforward to develop, given the blueprints for developing HCV replicon assays. Working out the safety issues of compound development would still be challenging, given treatment during pregnancy, but maybe there’s options for development of Zika prophylactics? As far as industry-government cooperation goes, easier said than done – but nothing ventured, nothing gained. Seems like there also needs to be cooperative funding strategies for developing (and making available) flavivirus assays ahead of the curve, before the next flavivirus (west nile, dengue, …) outbreak occurs.

    1. anon says:

      “weak HCV inhibitors could show significant Zika potency”

      I get what you’re saying, but is there really any inherent reason to believe weak inhibitors of HCV could have a higher chance of being potent towards Zika? Or is it just because there’s more of them.

  7. Kevin says:

    Yet another use for Niclosamide. I have seen so many clinicians propose Niclosamide as a lead for their novel cancer targets that I have bookmarked the pubchem bioassay page for CID4477.

    1. HTSguy says:

      Wow, a drug that Pubchem actually managed to limit to one CID! What a concept.

    2. Zander says:

      PAIN?

  8. Mach says:

    Nope- that’s a great last line where the potential benefit and I assume Mother infected by a bacterium outweighed risk to the fetus. With Microcephaly looming a normal dose can’t hurt. And if it’s OK for a bacterial infection why not a viral? You can find tox studies used much higher doses and these molecules useful.

    1. Nope nope says:

      Well, the catch is that you don’t know exactly who had been infected with Zika – you can’t just prescribe minocycline to all pregnant women and be OK with the number of birth defects. No doctor would open themselves up to that impending lawsuit.

      Maybe your plan would work if we knew exactly which moms were infected with Zika – they could be told the risks, etc., and decide for themselves. But that’s not where we are at the moment.

  9. metaphysician says:

    I suppose the hope here is to come up with a treatment safe enough to be used prophylacticly? Because, given the lack of symptoms in most Zika infections, it seems treating only known cases would be kind of useless.

  10. OLuwadamilola olugbile says:

    I believe most people are yet to come to terms with how devastating Zika is because those “Zika Babies” are still young. It is when they reach puberty, especially during their adolescent years that the world will pay full attention to Zika, Malaria, fever, and mosquitoes when we begin to witness hundred of thousands of deformed and cognitively distorted adults.

    I personally think a vaccination should be developed just like polio in order to prevent future recurring of the Zika virus.

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