Peptides as SUB1 inhibitors

The project concerns development of peptidase inhibitors with potential interest in the treatment of Malaria. Malaria is the most important human parasitic disease and multi-resistant parasites seriously threaten its treatment and control. The situation strengthens the constant need to fuel the antimalarials pipeline with candidates active on new targets, expressed at essential stages of Plasmodium. 

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The egress of merozoites from infected host cells is such a pivotal step that strictly depends upon parasite proteases, including a novel highly promising target, the Plasmodium-specific subtilisin SUB1, for which no useful inhibitor has been discovered yet. SUB1 plays a key role in the egress from hepatocytes and erythrocytes, including for male gametes (involved in parasite’s transmission via the Anopheles vector), indicating that an inhibitor would have both prophylactic and therapeutic value and obey to most severe WHO’s criteria of future antimalarials, i.e. targeting all stages of parasite life cycle. Based on Hosts’ promising results, including the resolution of crystallographic structures of SUB1-inhibitor complexes, the SUBUN project aimed at identifying highly potent and selective SUB1 inhibitors, active against parasite growth in vitro and in vivo. 

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This project combined expertise in molecular design, medicinal chemistry, biochemistry, structural biology and parasitology.