Identification of Viral OTU-Like Plasmodium Parasite Proteases and Development of Antimalarial DUB Inhibitors

Abstract

OTU proteases are key proteins of intracellular parasites that antagonize the cellular defenses following the entry into the host cells. Intriguingly, three of the parasitic plasmodium species causing malaria have uncharacterized viral OTU protein-like proteins. However, structure, function or inhibitors of these OTU-like proteins have not been previously reported. We have performed modeling, drug screening, deconjugating assays and determined novel inhibitors of OTU-like proteins of P.falciparum, P.vivax, and P.yoelii species. Malarial OTU (mOTU) activities were shown by deconjugation assays, intracellular ubiquitinylated protein content analysis, and gene expression analysis. We screened a library of anti-malarial small molecules to determine potent mOTU inhibitors and identified four mOTU inhibitors that could inhibit in vitro and in vivo mOTU DUB protease activity. Some of these small molecules demonstrate anti-malarial activities. These findings suggest that targeting viral OTU-like Plasmodium parasite proteases is a plausible strategy to develop new anti-malarial therapies.