Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy

Ryan D. Imhoff, Melissa R. Rosenthal, Kutub Ashraf, Purnima Bhanot, Caroline L. Ng, Daniel P. Flaherty

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium. Resistance to artemisinin-based combination therapies (ACTs), the current first-line treatment for malaria, has emerged in Asia, South America, and more recently Africa, where >90% of all malaria-related deaths occur. This has necessitated the identification and investigation of novel parasite proteins and pathways as antimalarial targets, including components of the ubiquitin proteasome system. Here, we investigate Plasmodium falciparum deubiquitinase ubiquitin C-terminal hydrolase L3 (PfUCHL3) as one such target. We carried out a high-throughput screen with covalent fragments and identified seven scaffolds that selectively inhibit the plasmodial UCHL3, but not human UCHL3 or the closely related human UCHL1. After assessing toxicity in human cells, we identified four promising hits and demonstrated their efficacy against asexual P. falciparum blood stages and P. berghei sporozoite stages.

Original languageEnglish (US)
Article number129458
JournalBioorganic and Medicinal Chemistry Letters
Volume94
DOIs
StatePublished - Oct 1 2023

Keywords

  • Anti-malaria drug discovery
  • Covalent inhibitor
  • Fragment-based inhibitor
  • Plasmodium falciparum UCHL3 Inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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