Design of proteasome inhibitors with oral efficacy in vivo against <i>Plasmodium falciparum</i> and selectivity over the human proteasome
Stanley C. Xie, Riley D. Metcalfe, Hirotake Mizutani, Tanya Puhalovich, Eric Hanssen, Craig J. Morton, Yawei Du, Con Dogovski, Shih‐Chung Huang, Jeffrey P. Ciavarri, Paul Hales, Robert Griffin, Lawrence H. Cohen, Bei-Ching Chuang, Sergio Wittlin, Ioanna Deni, Tomas Yeo, Kurt E. Ward, Daniel C. Barry, Boyin Liu, David L. Gillett, Benigno Crespo-Fernández, Sabine Ottilie, Nimisha Mittal, Alisje Churchyard, Daniel C J Ferguson, Anna Caroline Campos Aguiar, Rafael V. C. Guido, Jake Baum, Kirsten K. Hanson, Elizabeth A. Winzeler, Francisco‐Javier Gamo, David A. Fidock, Delphine Baud, Michael W. Parker, Stephen Brand, Lawrence R. Dick, Michael D. W. Griffin, Alexandra E. Gould, Leann Tilley
Abstract
Significance Here, we describe inhibitors of the Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from inhibitors developed to treat cancer, derivatives were designed and synthesized with the aim of increasing potency against the Plasmodium proteasome and decreasing activity against the human enzyme. Biochemical and cellular assays identified compounds that exhibit selectivity and potency, both in vitro and in vivo, at different stages of the parasite’s lifecycle. Cryo-electron microscopy revealed that the inhibitors bind in a hydrophobic pocket that is structurally different in the human proteasome—underpinning their selectivity. The work will help develop antimalarial therapeutics, which are desperately needed to treat a disease that kills nearly half a million people annually.