ジャーナル: Proc Natl Acad Sci U S A / 年: 2021 タイトル: Design of proteasome inhibitors with oral efficacy in vivo against and selectivity over the human proteasome. 著者: 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 ...著者: 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 / David L Gillett / Benigno F Crespo-Fernandez / Sabine Ottilie / Nimisha Mittal / Alisje Churchyard / Daniel Ferguson / Anna Caroline C 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 / 要旨: The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and ...The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of compared with a human cell line and exhibit high potency against field isolates of and 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 infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to 20S than to human constitutive 20S (20Sc). Comparison of the cryo-electron microscopy (EM) structures of 20S and 20Sc in complex with MPI-5 and 20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in , underpinning the design of potent and selective antimalarial proteasome inhibitors.