Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Autor: Lawong A; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Gahalawat S; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Ray S; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Ho N; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Han Y; Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Ward KE; Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA., Deng X; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Chen Z; Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Kumar A; Department of Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Xing C; Department of Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Hosangadi V; Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA., Fairhurst KJ; Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA., Tashiro K; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Liszczak G; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Shackleford DM; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Katneni K; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Chen G; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Saunders J; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Crighton E; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Casas A; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Robinson JJ; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Imlay LS; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Zhang X; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Lemoff A; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA., Zhao Z; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Angulo-Barturen I; The Art of Discovery, Biscay Science and Technology Park, Astrondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain., Jiménez-Díaz MB; The Art of Discovery, Biscay Science and Technology Park, Astrondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain., Wittlin S; Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland; University of Basel Kreuzstrasse 2, 4123 Allschwil, Switzerland., Campbell SF; Medicines for Malaria Venture, 1215 Geneva, Switzerland., Fidock DA; Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Columbia University Irving Medical Center, New York, NY 10032, USA., Laleu B; Medicines for Malaria Venture, 1215 Geneva, Switzerland., Charman SA; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia., Ready JM; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Electronic address: joseph.ready@utsouthwestern.edu., Phillips MA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Electronic address: margaret.phillips@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Cell chemical biology [Cell Chem Biol] 2024 Aug 15; Vol. 31 (8), pp. 1503-1517.e19. Date of Electronic Publication: 2024 Jul 30.
DOI: 10.1016/j.chembiol.2024.07.001
Abstrakt: 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 (Pfβ5). 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 Pfβ5 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.
Competing Interests: Declaration of interests B.L. is a Medicines for Malaria Venture (MMV) employee. J.M.R., S.F.C., B.L., S.G., S.A.C., and M.A.P. are inventors on a patent application covering the described compounds.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: