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22 August 2016
Anette Breindl / BioWorld
A single compound was able to rid mice of three separate parasitic infections, opening the possibility of developing a relatively broad-spectrum approach against the three, which are collectively known as kinetoplastids.
Chagas disease, leishmaniasis and African human trypanosomiasis, or sleeping sickness, collectively affect about 20 million people, though the caseload differs greatly between the three.
According to the Thomson Reuters Incidence & Prevalence Database (IPD), there are about 12 million cases globally of leishmaniasis. Estimates of the global prevalence of Chagas disease vary between 8 million and 14 million, and the prevalence estimates of sleeping sickness reported in the IPD range between 100,000 and 500,000.
The outlook for their epidemiology differs as well. Sleeping sickness has declined by 85 percent and is now largely confined to a few failed or fragile states in Central Africa, and the World Health Organization lists eradication as a goal.
In contrast, leishmaniasis is present in tropical and subtropical regions globally, and Chagas disease, which was once confined to Latin America, has spread and is now a global problem, though cases are still concentrated in South and Central America.
The new compound, GNF6702, came out of a screening effort that looked at the ability of more than 3 million compounds to inhibit the growth of three parasites: Trypanosoma cruzi, which causes Chagas disease, Leishmania donovani, which is the major cause of the more serious, visceral form of leishmaniasis, and Trypanosoma brucei, the culprit behind sleeping sickness.
That screening resulted in a number of hits, including a precursor of GNF6702. The team selected that precursor for a combination of reasons, including decent potency and selectivity, and the fact that its structure was a "good starting point" for medicinal chemistry, Frantisek Supek told BioWorld Today. Supek is a researcher at the Genomics Institute of the Novartis Research Foundation and the corresponding author of the paper reporting the findings, which appeared in the Aug. 8, 2016, advance online issue ofNature.
Supek said that although the paper's main focus was a practical one, on drug discovery, "we also came across several findings which have implications for more fundamental science" in the work.
Though "many groups working on parasites are using a similar approach to what we do" in beginning with phenotypic screening, Supek said that his team is the first, to his knowledge, which comprehensively outlines the strategy.
Supek and his team also went beyond identifying a broad-spectrum compound to identifying the target of that compound. In the case of GNF6702, that target turned out to be an allosteric site on the parasite proteasome, meaning that the drug does not target the proteasome's active site directly.
"We are not sure [yet] if this site is unique for kinetoplastids or if it is present also on human proteasomes," Supek said, though the team has demonstrated that GNF6702 does not affect the human proteasome. Parasite proteasomes, on the other hand, were sensitive to proteasome inhibitor Velcade (bortezomib,Takeda Oncology Co.), though Supek noted that this sensitivity at the cell culture level should not be taken as an indication that Velcade, which has a narrow therapeutic index and needs to be given as an infusion, might have a future as an antiparasitic agent. "In general, my assessment is that [Velcade] is too toxic to be used with patients who have other alternatives," he said.
Earlier this year another group, led by researchers from Stanford University and the British MRC Laboratory of Molecular Biology, described developing inhibitors of the Plasmodium falciparum proteasome, as a promising antimalarial drug discovery approach.
The other team, Supek said, was focused on the proteasome to begin with, whereas "we came from a very different angle... We didn't care what the compound does, as long as it has promise for treating patients."
The convergence of the two separate approaches on the proteasome suggests the structure might be a promising general antiparasitic drug target.
Even if the proteasome is broadly useful, that does not necessarily mean that the best strategy would be to be to develop broader-spectrum drugs against it.
While a compound that targets even more than three parasite proteasomes is theoretically possible, Supek said that in his opinion, it's "probably better to develop more specific drugs" to improve selectivity.
"Some of these parasites reside in patients in very different organs," he pointed out. In the studies his team has published in Nature, "we had to use a very high dose" to eradicate T. brucei from the brain, leading to increased toxicity risk.
Currently, Supek and his colleagues are doing more detailed toxicity studies on GNF6072 as well as further work on identifying proteasome-targeting drugs.
"It's possible that the compounds which came up [in our screen] are not going to make it to the clinic," he said. But even if that turns out to be the case, his team's identification of the proteasome as a promising target means that work would not have to start completely from scratch if the compounds do fail.
The RMI group has completed sertain projects
The RMI Group has exited from the capital of portfolio companies:
Marinus Pharmaceuticals, Inc.,
Syndax Pharmaceuticals, Inc.,
Atea Pharmaceuticals, Inc.