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Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.
Lawong, Aloysus; Gahalawat, Suraksha; Ray, Sneha; Ho, Nhi; Han, Yan; Ward, Kurt E; Deng, Xiaoyi; Chen, Zhe; Kumar, Ashwani; Xing, Chao; Hosangadi, Varun; Fairhurst, Kate J; Tashiro, Kyuto; Liszczak, Glen; Shackleford, David M; Katneni, Kasiram; Chen, Gong; Saunders, Jessica; Crighton, Elly; Casas, Arturo; Robinson, Joshua J; Imlay, Leah S; Zhang, Xiaoyu; Lemoff, Andrew; Zhao, Zhiyu; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wittlin, Sergio; Campbell, Simon F; Fidock, David A; Laleu, Benoît; Charman, Susan A; Ready, Joseph M; Phillips, Margaret A.
Affiliation
  • 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.
Cell Chem Biol ; 31(8): 1503-1517.e19, 2024 Aug 15.
Article in En | MEDLINE | ID: mdl-39084225
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 ß5 active-site (Pfß5). 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] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 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 ß5/ß6/ß3 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Plasmodium falciparum / Proteasome Inhibitors / Antimalarials Limits: Animals / Female / Humans Language: En Journal: Cell Chem Biol Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Plasmodium falciparum / Proteasome Inhibitors / Antimalarials Limits: Animals / Female / Humans Language: En Journal: Cell Chem Biol Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States