Here’s a new paper with a surprise: a small molecule that appears to be very effective against malaria, with what may be a high barrier to developing resistance (C&E News coverage here). It’s from a large multicenter (multicontinent) team, and the chemical matter has its origins at Sanofi. The idea was to search for human homologs of targets that are present in several human blood-borne parasite organisms (P. falciparum, T. brucei, T. cruzi, and L. donvani) and mine Sanofi’s drug discovery data for compounds that showed activity against these.
With 33 targets on the list, the group found 450 compounds by data-mining, and also included 350 other compounds that were known to hit high-priority human targets. 120 of these 800 showed some activity against cultured P. falciparum, and got a really high hit rate (15%) at 1 micromolar activity or below (IC50). Further screening for compound properties and a screen of analogs of the hits worked things down to six chemical scaffolds for med-chem optimization. The paper describes one of those series, an acylguanidine chemotype that came ultimately from compounds like cariporide, which targets sodium ion/proton exchange. Some past program had taken that core and made azo-linked dimers of it, and that’s what hit in the assays. Further optimization by the medicinal chemists led to an alkyne linker and some variation in the aryl substitution pattern, leading to MMV688533, shown at right. This kept the same nanomolar potency, while improving solubility and intestinal permeability.
The compound kills blood-stage parasites (not liver-stage, etc.), and it does a very good job of that. Against both cultured strains and patient isolates (from Uganda and New Guinea), it maintained strong activity, and (most interestingly) it showed the same potency against strains that are resistant to all the known antimalarials. Whatever the mechanism is, it’s something new, and that’s badly needed in this area. Mouse models of infection showed a 90% efficacy dose of 2 mg/kg, with very rapid onset of parasite destruction, and in fact one dose at at least 5 mpk was as effective as a 50 mg/kg dose of dihydroartemisinin, which is currently the fastest-acting antimalarial known. After further pharmacokinetics in rodents and dogs, the a single 30mg dose in an average-sized human is predicted to keep blood concentrations at parasite-killing levels for at least 96 hours (enough for two replication cycles of the parasite in blood cells) and this should reduce the organism’s population in the blood by at least 6 log units (!). A single dose of 66mg is predicted to lead to a 12-log reduction, which is extremely promising for a one-pill cure.
The compound does not set off genotoxicity assays, is not a P450 inducer or inhibitor, does not show any cardiovascular safety signal in animal infusion models, and in panels of other ion channels and GPCRs, the most potent activities are at 10 micromolar or above. Preliminary 2-week tox in rats and dogs led to a no-effect level that is still 14-fold higher than the projected levels after a single 30mg dose. This is just the sort of thing you want to see for recommending human clinical trials.
Another promising finding came from attempts to induce resistance. Constant-level dosing for 60 days on P. falciparum cultures led to no development of resistance at all, and ramping up the exposure over a six-month period showed only 2x to 5x loss of potency. Sequencing of these resistant organisms showed single-nucleotide polymorphisms in five genes, two of which are conserved but are of unknown function. The other three were an Eps15 homology domain (EHD)–containing protein, a putative RNA pseudouridylate synthase (which converts uracils to pseudouridines), and a putative adenosine 5′-triphosphate synthase (C/AC39) subunit. All the resistant clones that they sequenced, though, had one sort of mutation or another in one of those two unknown-function proteins, which suggests that it at least might be a key player in developing resistance (and thus possibly to the compound’s mechanism as well). The highest level of resistance was seen in a clone that had this gene and the Eps15HD one both mutated.
You have to be careful with these assignments, of course – you can also see bounce-shot secondary-effect mechanisms when you’re doing these experiments, but this is definitely the first place to look. Indeed, further experiments with conditional knockdown of both of these genes (through a tetracycline-driven expression mechanism) showed that dialing down their expression did not kill the parasites: they can survive without them. So it appears that neither one of them is a direct target of MMV688533 – they presumably help out with survival with some downstream mechanisms. The actual target of the drug remains unknown, but (as mentioned) it’s clearly different from other antimalarials. For one thing, when you do those sorts of resistance experiments with the known drugs, you get completely different sets of protein mutations in response. The best guess so far is that the new compound might be hitting vesicular trafficking or lipid storage mechanisms, but it’s still pretty hazy.
So this compound appears to be heading into Phase I human trials, and it’s going to be of great interest to see what happens there. The human dose levels will get refined, and if there are no show-stoppers then it’ll move on to Phase II trials with real malaria patients. Here’s hoping for a straightforward path through the clinic: the world very much needs a single-dose malaria therapy with a new mode of action. That along with the recent and promising vaccine work give a person hope that we might actually be able to remove a vast amount of human suffering and early death from the world. Plasmodium parasites have been having their way with us for millions of years, and the 21st century started off with a strong reduction in cases and deaths. But this seems to have plateaued at roughly 200 million cases and four hundred thousand deaths a year, and it will be a great day when we can do something about it for good.
The post A New Small Molecule Candidate for Malaria first appeared on In the Pipeline.
