Affordable Access

deepdyve-link
Publisher Website

High-Content Screening of the Medicines for Malaria Venture Pathogen Box for Plasmodium falciparum Digestive Vacuole-Disrupting Molecules Reveals Valuable Starting Points for Drug Discovery.

Authors
  • Tong, Jie Xin1
  • Chandramohanadas, Rajesh2
  • Tan, Kevin Shyong-Wei3
  • 1 Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. , (Singapore)
  • 2 Pillar of Engineering Product Development, Singapore University of Technology and Design, Singapore. , (Singapore)
  • 3 Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [email protected] , (Singapore)
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
Mar 01, 2018
Volume
62
Issue
3
Identifiers
DOI: 10.1128/AAC.02031-17
PMID: 29311064
Source
Medline
Keywords
License
Unknown

Abstract

Plasmodium falciparum infections leading to malaria have severe clinical manifestations and high mortality rates. Chloroquine (CQ), a former mainstay of malaria chemotherapy, has been rendered ineffective due to the emergence of widespread resistance. Recent studies, however, have unveiled a novel mode of action in which low-micromolar levels of CQ permeabilized the parasite's digestive vacuole (DV) membrane, leading to calcium efflux, mitochondrial depolarization, and DNA degradation. These phenotypes implicate the DV as an alternative target of CQ and suggest that DV disruption is an attractive target for exploitation by DV-disruptive antimalarials. In the current study, high-content screening of the Medicines for Malaria Venture (MMV) Pathogen Box (2015) was performed to select compounds which disrupt the DV membrane, as measured by the leakage of intravacuolar Ca2+ using the calcium probe Fluo-4 AM. The hits were further characterized by hemozoin biocrystallization inhibition assays and dose-response half-maximal (50%) inhibitory concentration (IC50) assays across resistant and sensitive strains. Three hits, MMV676380, MMV085071, and MMV687812, were shown to demonstrate a lack of CQ cross-resistance in parasite strains and field isolates. Through systematic analyses, MMV085071 emerged as the top hit due to its rapid parasiticidal effect, low-nanomolar IC50, and good efficacy in triggering DV disruption, mitochondrial degradation, and DNA fragmentation in P. falciparum These programmed cell death (PCD)-like phenotypes following permeabilization of the DV suggests that these compounds kill the parasite by a PCD-like mechanism. From the drug development perspective, MMV085071, which was identified to be a potent DV disruptor, offers a promising starting point for subsequent hit-to-lead generation and optimization through structure-activity relationships.

Report this publication

Statistics

Seen <100 times