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.
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!