Design of proteasome inhibitors with oral efficacy in vivo against and selectivity over the human proteasome.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Proceedings of the National Academy of Sciences of the United States of America, Volume: 118, Issue: 39
September 28, 2021
Stanley C Xie SC, Riley D Metcalfe RD, Hirotake Mizutani H, Tanya Puhalovich T, Eric Hanssen E, Craig J Morton CJ, Yawei Du Y, Con Dogovski C, Shih-Chung Huang SC, Jeffrey Ciavarri J, Paul Hales P, Robert J Griffin RJ, Lawrence H Cohen LH, Bei-Ching Chuang BC, Sergio Wittlin S, Ioanna Deni I, Tomas Yeo T, Kurt E Ward KE, Daniel C Barry DC, Boyin Liu B, David L Gillett DL, Benigno F Crespo-Fernandez BF, Sabine Ottilie S, Nimisha Mittal N, Alisje Churchyard A, Daniel Ferguson D, Anna Caroline C Aguiar ACC, Rafael V C Guido RVC, Jake Baum J, Kirsten K Hanson KK, Elizabeth A Winzeler EA, Francisco-Javier Gamo FJ, David A Fidock DA, Delphine Baud D, Michael W Parker MW, Stephen Brand S, Lawrence R Dick LR, Michael D W Griffin MDW, Alexandra E Gould AE, Leann Tilley L

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.

Courtesy of the U.S. National Library of Medicine