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TitleIdentification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.
Journal, issue, pagesCell Chem Biol, Vol. 31, Issue 8, Page 1503-1517.e19, Year 2024
Publish dateAug 15, 2024
AuthorsAloysus Lawong / Suraksha Gahalawat / Sneha 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 J Robinson / Leah S Imlay / Xiaoyu Zhang / Andrew Lemoff / Zhiyu Zhao / Iñigo Angulo-Barturen / María Belén Jiménez-Díaz / Sergio Wittlin / Simon F Campbell / David A Fidock / Benoît Laleu / Susan A Charman / Joseph M Ready / Margaret A Phillips /
PubMed AbstractMalaria 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 ...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) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His-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.
External linksCell Chem Biol / PubMed:39084225 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

43746

8w2f

EMDB-43746, PDB-8w2f:
Plasmodium falciparum 20S proteasome bound to an inhibitor
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

PDB-1ae6:
IGG-FAB FRAGMENT OF MOUSE MONOCLONAL ANTIBODY CTM01

Source
  • plasmodium falciparum 3d7 (eukaryote)
KeywordsCYTOSOLIC PROTEIN/INHIBITOR / Malaria / Plasmodium falciparum / proteasome / drug discovery / CYTOSOLIC PROTEIN / CYTOSOLIC PROTEIN-INHIBITOR complex

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