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

drug discovery drug resistance malaria plasmodium proteasome

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
24 Jul 2024
Historique:
received: 04 03 2024
revised: 08 05 2024
accepted: 03 07 2024
medline: 1 8 2024
pubmed: 1 8 2024
entrez: 31 7 2024
Statut: aheadofprint

Résumé

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

Identifiants

DOI: 10.1016/j.chembiol.2024.07.001 PMID: 39084225
pubmed: 39084225
pii: S2451-9456(24)00278-2
doi: 10.1016/j.chembiol.2024.07.001
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Aloysus Lawong (A)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Suraksha Gahalawat (S)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Sneha Ray (S)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Nhi Ho (N)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Yan Han (Y)

Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Kurt E Ward (KE)

Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA.

Xiaoyi Deng (X)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Zhe Chen (Z)

Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Ashwani 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.

Chao 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.

Varun Hosangadi (V)

Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA.

Kate J Fairhurst (KJ)

Department of Microbiology and Immunology, and Columbia University Irving Medical Center, New York, NY 10032, USA.

Kyuto Tashiro (K)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Glen Liszczak (G)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

David M Shackleford (DM)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Kasiram Katneni (K)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Gong Chen (G)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Jessica Saunders (J)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Elly Crighton (E)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Arturo Casas (A)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Joshua J Robinson (JJ)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Leah S Imlay (LS)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Xiaoyu Zhang (X)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Andrew Lemoff (A)

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Zhiyu Zhao (Z)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Iñigo Angulo-Barturen (I)

The Art of Discovery, Biscay Science and Technology Park, Astrondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain.

María Belén Jiménez-Díaz (MB)

The Art of Discovery, Biscay Science and Technology Park, Astrondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain.

Sergio Wittlin (S)

Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland; University of Basel Kreuzstrasse 2, 4123 Allschwil, Switzerland.

Simon F Campbell (SF)

Medicines for Malaria Venture, 1215 Geneva, Switzerland.

David A 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.

Benoît Laleu (B)

Medicines for Malaria Venture, 1215 Geneva, Switzerland.

Susan A Charman (SA)

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Joseph M 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.

Margaret A 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.

Classifications MeSH