Journal article

Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum 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 Ciavarri, Paul Hales, Robert J Griffin, Lawrence H Cohen, Bei-Ching Chuang, Sergio Wittlin, Ioanna Deni, Tomas Yeo, Kurt E Ward, Daniel C Barry, Boyin Liu Show all

Proc Natl Acad Sci U S A | Proceedings of the National Academy of Sciences | Published : 2021

Abstract

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dos..

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