Hi Everybody,

In addition to celebrating the GO Fight Against Malaria project's first birthday today, I have some other good news to share with all of you. In the results of Exp. 5, we've discovered some promising new inhibitors of ENR (enoyl-acyl-carrier-protein reductase). This is an example of targeting malaria side-ways, instead of head on. The first collaborators we found who were able and willing to experimentally assess the predictions from GO Fight Against Malaria were in Peter Tonge's lab at Stony Brook University. Peter Tonge is a world-renowned expert in tuberculosis research. Since the drug target InhA from Mycobacterium tuberculosis is structurally similar to the ENR target from Plasmodium falciparum, Mtb InhA was included as part of these GO Fight Against Malaria experiments against ENR. I analyzed the docking results against the TB targets in Experiment 5, and I asked our collaborators to order 20 candidate compounds. 19 compounds actually arrived, but 3 were not soluble. Of the 16 soluble compounds that were tested in biological assays by Weixuan Yu in the Tonge lab, 7 compounds inhibited Mtb InhA activity by ~ 30 to 70% at a 100 micro-Molar concentration. The best hit displayed an IC50 value of approximately 40 micro-Molar. The Tonge lab is now performing additional assays to fully characterize the potency and kinetic properties of these new InhA inhibitors.

There are 2 million tuberculosis-related deaths per year, which makes Mycobacterium tuberculosis the deadliest bacteria on Earth. Mtb InhA is the target for the drug isoniazid (INH). INH is the drug usually administered to treat latent tuberculosis infections, and it is used in combination therapies to treat active tuberculosis disease. But drug-resistant mutant "superbugs" of Mtb are hampering the clinical effectiveness of INH treatment. I designed these experiments against ENR and InhA to specifically counteract the main mechanism that is used by Mtb to evade treatment with INH. Consequently, discovering a novel, 40 micro-Molar inhibitor of Mtb InhA should eventually help us advance the treatment of multi-drug-resistant and extremely-drug-resistant tuberculosis infections. I'll write a research manuscript on these results within the next few months and submit the paper for publication. Hopefully, it might be published in the middle of 2013 (but we'll have to see how the peer-review process goes). Wish us luck.

I'll use the same tools and strategies that led to the discovery of these successful new inhibitors against Mtb InhA when I analyze the docking calculations against ENR from Plasmodium falciparum. There's also a decent chance that some of these 16 candidates against InhA might also be good candidates against Pf ENR. I'll let you know what we find out.

Thank you very much for all of your support!

Cheers,
Alex L. Perryman, Ph.D.

PS--Have a very happy Thanksgiving!