Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria
Aloysus K. Lawong, Suraksha Gahalawat, S. Ray, Nhi Ho, Yan Han, Kurt E. Ward, Xiaoyi Deng, Zhe Chen, Ashwani Kumar, Chao Xing, Varun Hosangadi, Kate J. Fairhurst, Kyuto Tashiro, Glen Liszczak, David M. Shackleford, Kasiram Katneni, Gong Chen, Jessica Saunders, Elly Crighton, Arturo Casas, Joshua Robinson, Leah S. Imlay, Xiaoyu Zhang, Andrew Lemoff, Zhiyu Zhao, Íñigo Angulo‐Barturen, Marı́a Belén Jiménez-Dı́az, Sergio Wittlin, Simon F. Campbell, David A. Fidock, Benoı̂t Laleu, Susan A. Charman, Joseph M. Ready, Margaret A. Phillips
Abstract
Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum ( Pf ) parasites revealed point mutations in the Pf_ proteasome β5 active-site ( Pf β5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >10 9 ) and was synergistic with dihydroartemisinin. Pf_ proteasome purification was facilitated by His 8 -tag introduction onto β7. Inhibition of Pf β5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_ proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.