Novel inhibitors of malaria proteasome

Proteasome inhibitors can kill Plasmodium spp.. However, lack of malaria-specific proteasome inhibitors that spare human proteasomes has so far precluded treating malaria with drugs like bortezomib, carfilzomib and ixazomib, which have significant toxicity. There is an urgent need to develop malaria-specific proteasome inhibitors. Our past work, including substrate profiling, enzymology, structure-guided rational design and high throughput screening, led to discovery of the first species-selective proteasome inhibitors (active against mycobacterial proteasomes but not human proteasomes) as well as highly isoform-selective proteasome inhibitors (active against the human immunoproteasome but not the human constitutive proteasome). Informed by those experiences, we collaborated with Dr. Laura Kirkman, parasitologist and co-PI, to identify a novel class of compounds that kill P. falciparum in vitro but spare mammalian cells. These compounds inhibit the P. falciparum proteasome (Pf20S) 5 subunit potently, noncovalently and noncompetitively. The chemophore, subunit specificity, noncovalent reactivity and noncompetitive mode of inhibition of these compounds are distinctive compared to a Pf20S 2 inhibitor recently reported by Bogyo’s team, thereby offering an independent shot on goal against a well validated target, an opportunity to overcome resistance to one agent by using the other, and the possibility of synergistic results from using both, if they each lead to drugs. The inhibitors are highly potent in inhibiting growth of P. falciparum at erythrocytic, liver, and gametocyte stages and are equally effective against P. falciparum isolates that are sensitive or resistant to current drugs. 

NIH project details

Drug-based Strategies
Product Development

Feb 2017 — Jan 2020

$466,125

United States