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Article Abstract
Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the Na pump (ATP4). ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na concentration. Resistance selections on parasites with two α-azacyclic acetamide analogs identified mutations in ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming ATP4 as the target. ATP4 is a well-established antimalarial target, and identification of additional ATP4 inhibitors provides alternative avenues to disrupt its function.
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Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the Na pump ( ATP4).
View Article and Find Full Text PDFThe sodium efflux pump ATP4 is a leading antimalarial target, but suffers from a lack of high-resolution structural information needed to identify functionally important features in conserved regions and guide rational design of next generation inhibitors. Here, we determine a 3.7Å cryoEM structure of ATP4 purified from CRISPR-engineered parasites, revealing a previously unknown, apicomplexan-specific binding partner, ABP, which forms a conserved, likely modulatory interaction with ATP4.
View Article and Find Full Text PDFAntimalarials Targeting the Malaria Parasite Cation ATPase ATP4 (PfATP4).
Curr Top Med Chem
March 2023
Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wrocław, 50-383, Wrocław, Poland.
Malaria, caused by parasites of the Plasmodium species and transmitted through the bites of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the search for new molecules with activity against this parasite.
View Article and Find Full Text PDFCation ATPase (ATP4) Orthologue Replacement in the Malaria Parasite Plasmodium knowlesi Reveals Species-Specific Responses to ATP4-Targeting Drugs.
mBio
October 2022
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Several unrelated classes of antimalarial compounds developed against Plasmodium falciparum target a parasite-specific P-type ATP-dependent Na pump, PfATP4. We have previously shown that other malaria parasite species infecting humans are less susceptible to these compounds. Here, we generated a series of transgenic Plasmodium knowlesi orthologue replacement (OR) lines in which the endogenous locus was replaced by a recodonized atp4 () coding region or the orthologous coding region from P.
View Article and Find Full Text PDFA G358S mutation in the Plasmodium falciparum Na pump PfATP4 confers clinically-relevant resistance to cipargamin.
Nat Commun
September 2022
Research School of Biology, Australian National University, Canberra, ACT, 2600, Australia.
Article Synopsis
- * The G358S mutation in PfATP4 enables parasites to tolerate higher concentrations of these inhibitors while remaining susceptible to other antimalarials not targeting PfATP4.
- * Results indicate that PfATP4 mutations decrease drug sensitivity but do not affect parasite growth or spread, suggesting the need for testing inhibitor combinations to counteract potential resistance.