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Three Diseases at Once?

Here’s a really nice paper that points out a possible way to attack three terrible parasitic diseases at the same time: Chagas disease, leishmaniasis, and sleeping sickness, all caused by related protozoan organisms. This new effort, a multicenter collaboration between labs at Novartis, York, Washington, and the Wellcome Trust labs at Glasgow, tested a large screening collection against all three organisms looking for overlap. A lead compound (GMF5343) was optimized to give GNF6702. Note that the key change was switching out the heterocyclic core; work on the side chains did the rest. GNF3849 looks like a pretty good compound, but it wasn’t selective enough in mammalian cell counterscreens, whereas GNF6702 doesn’t touch them at all.

GNF progression

So what are these compounds doing? One way to find that out in an infectious disease organism is to keep hitting it with low doses of the compound and seeing if you can breed resistant strains – then you sequence those and look for what changed. Inducing resistance to compounds in the series wasn’t easy, but some of the analogs (after months of selection pressures) did yield strains that had mutations in several genes, with two changes in a gene coding for the proteasome beta-4 subunit. The proteasome has already been a target in antimalarial therapies, and it seemed a likely candidate here as well. Specific substrate assays proved that the chymotrypsin-like activity of the proteasome was indeed strongly inhibited by GNF6702, while the mutant strains were far less susceptible.

Interestingly (and in contrast to the known proteasome-targeting drugs), the compound has a noncompetitive mechanism for enzyme inhibition. As mentioned, it’s clean against mammalian proteasomes, which happen to have a sequence closer to the resistant mutant forms. This compound was taken into several rodent models of disease, and showed substantial activity in all of them, eradicating parasites from several completely different tissues and cellular compartments.

The paper says that GNF6702 is currently in preclinical tox testing, and I wish everyone involved luck if it does indeed move on to human trials. Something like this could be a real advance – a new compound, a new mechanism of action, activity across several diseases, and very slow onset of resistance. It may yet turn out these diseases will end up needing separate drugs in the end, but if just one could be distributed instead, that would also be a good feature in many of the areas where these diseases cause the most suffering. Congratulations to all involved!

18 comments on “Three Diseases at Once?”

  1. Peter Kenny says:

    This looks like a most encouraging development! Sometimes a compound targeted at one parasite can hit other classes of parasite and the cysteine protease inhibitor K777 which was of interest for Chagas also shows activity in a murine schistosomiasis model. There are some points of interest of general medicinal chemistry interest as well such as the bioisosteric relationship between 1,2,4-triazole and oxazole. The N1 and N7 ‘lone pairs’ will tend to reinforce each other (see discussion of 1,8-naphthyridine in article that I’ve linked as URL for this comment) in an analogous manner to those of pyridazine.

    On an unrelated note, it’d be interesting to hear what advice advocates for Fsp3 as a design parameter would have had for the project team with respect to the acceptability of the hit and to the best way to optimise it.

    1. Phil says:

      I guess there is still uncharted chemical space in flatland too!

    2. The passive voice is used to an alarming extent. Verb subjects are hidden and ambiguous. A parody is difficult to achieve, as satire cannot exceed the original!

      1. Phil says:

        Derek, your bot filter must be malfunctioning. I think Hemingway got in.

    3. Julie says:

      “The N1 and N7 ‘lone pairs’ will tend to reinforce each other (see discussion of 1,8-naphthyridine in article that I’ve linked as URL for this comment) in an analogous manner to those of pyridazine.”

      could you re-post the link?

      1. Snapple says:

        The URL is the poster’s name. It allows you to use the name of the commenter as a hyperlink.

      2. Peter Kenny says:

        Hope you found found the link, Julie, and thanks to Snapple for clarify my original comment. Here are the article details:
        J Med Chem, 2016, 59 (9), pp 4278–4288 (DOI:10.1021/acs.jmedchem.5b01946)

        When In The Pipeline was hosted on Corante, I recall that comments would not be accepted if they contained hyperlinks and posting links as one’s name was the best way to share them. Don’t know if this still the case for the new hosting arrangements.

        1. julie says:

          got it! thanks to both of you!

  2. tnr says:

    If the compound makes it to clinical trials, this would be a nice application for a class of clinical trials called ‘basket trials’. These have been used in oncology and the idea is to run a clinical trial with a compound across a spectrum of diseases simultaneously. There are difficult statistical issues regarding choice of endpoint in each of the diseases, sample sizes, and how to analyze the data at the end but it could provide an enormous time and cost benefit as opposed to attacking the diseases in 3 separate clinical trials.

  3. qua says:

    You would have hoped that they could have designed the process so the most likely mutations will already have been foiled.

    1. Mol Biologist says:

      Agreed. There are a lot stones under water in “hit” methodology. IMO for species like Trypanosoma brucei, cruzi and L. donovani which are able to survive as obligate parasite these compounds will not work. They have evolved a variety of parasitic strategies to exploit their hosts. Subtle point is the journey through the blood. My choice would be the strategy to stop the delivery to a suitable place of residence. The residence is determined by tissue of interest and specific way to get the energy since they have no need for oxygen.

  4. Barry says:

    an anti-parasitic active against more than one disease isn’t novel. Consider:
    Ivermectin is a medication that is effective against many types of parasites.[1] It is used to treat head lice,[2] scabies,[3] river blindness,[4] strongyloidiasis,[5] and lymphatic filariasis, among others.[6]

  5. Mol Biologist says:

    Trypanosomes have unique feature and can give a free class to everybody in RNA editing Art or let’s cal it a Mutagenesis. Thank for first master-key due to kind involvement of blood-sucking insects. There is a loosy possibility of random invasion to tissue of interest but with RNA-editing tool or “Gut Feeling’ Is definitely the best strategy to use host resources. So IMO, to succeed we need to find a vulnerable site in their adaptation mechanism same as they did for us.

  6. Mol Biologist says:

    Trypanosomes have unique feature and can give a free class to everybody in RNA editing Art or let’s call it a Mutagenesis. Thank for first master-key due to kind involvement of blood-sucking insects. There is a loosy possibility of random invasion to tissue of interest but with RNA-editing tool or “Gut Feeling’ Is definitely the best strategy to use host resources. So IMO, to succeed we need to find a vulnerable site in their adaptation mechanism same as they did for

    1. Barry says:

      immune evasion is the stock in trade of a parasite afflicting vertebrates. Helminths seem to actively lull the system. Trypanosomes, instead, present an ever-shifting surface. Recent (partial) success with vaccines against malaria is achieved against a very slippery target

      1. Mol Biologist says:

        Barry, I did not even touch immune evasion. What I meant is the mechanism which utilizes communications through “bottle mail” or exosomes secreted by cells infected with obligate parasite in the environment and spread by the blood flow throughout the organism to deliver “mutual aid” or ready-made protein parts necessary for parasites same time ignoring host’s need.
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275648/

        1. tangent says:

          Wow, today I learned something totally new! Thanks for the paper.

  7. Nerd v geek says:

    Disappointing the authors did not reference earlier work by Baell and colleagues (European Journal of Medicinal Chemistry 66 (2013) 450-465) on a very similar chemotype also against T. cruzii. No work on mechanism in that paper but a simple SciFinder search would have easily identified the structures as important preceding work.

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