2. Academic Validation
  3. Identification of Compound 15 (MMV1581361) as a Pf ATP4 Inhibitor with Transmission-Blocking Activity and In Vivo Efficacy in a SCID Mouse Model of Malaria

Identification of Compound 15 (MMV1581361) as a Pf ATP4 Inhibitor with Transmission-Blocking Activity and In Vivo Efficacy in a SCID Mouse Model of Malaria

  • J Med Chem. 2026 Feb 26;69(4):3984-3998. doi: 10.1021/acs.jmedchem.5c01954.
Henry A Onyame 1,  Stephen Brand 2,  Delphin Baud 2,  Gregory S Basarab 3,  Natalie Hawryluk 4,  Stacie Canan 5,  Magdalene D Togoh 1,  Ramatu Abdulai 1,  Robert Eduku 1,  Mohammed Awal 1,  Richard Boakye Owoare 1,  Barsha Chatterjee 4,  Debasish Singha Roy 4,  Amal Kr Ray Mahapatra 4,  Soumyodip Bhowmik 4,  Proyasi Putatunda 4,  Benigno Crespo 6,  Laura Sanz 6,  David Calvo 6,  Sergio Wittlin 7,  Patrick K Tumwebaze 8,  Jeremy Borrows 2,  Richard K Amewu 1
Affiliations

Affiliations

  • 1 Drug Innovation Group, Department of Chemistry, University of Ghana, P. O. Box LG 56, Legon, Accra, Ghana.
  • 2 MMV Medicines for Malaria Venture, P.O. Box 1826, 20 rte de Pré-Bois, Geneva 15 1215, Switzerland.
  • 3 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7701, South Africa.
  • 4 TCG Lifesciences Pvt. Ltd., Block BN, Plot 7, Sector V, Salt Lake Electronics Complex, Kolkata, West Bengal 700 091, India.
  • 5 Elgia Therapeutics, Inc., 10686 Hunters Glen Drive, San Diego, California 92130, United States.
  • 6 Global Health Medicines R&D, GSK PTM Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
  • 7 Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, Basel 4002, Switzerland.
  • 8 Infectious Disease Research Collaboration, Molecular-Parasitology laboratory, P.O. Box 7475, Kampala, Uganda.
PMID: 41670300 DOI: 10.1021/acs.jmedchem.5c01954
Abstract

Focused structure-activity-relationship studies of MMV020136, 1, a whole-cell phenotypic screening hit originating from the Pathogen Box against the human malaria Parasite, Plasmodium falciparum, led to the identification of compound 15 (MMV1581361). Compound 15 retained nanomolar activity against drug-sensitive, drug-resistant, and field isolates of Plasmodium falciparum blood-stage parasites. It was found to display a moderate rate-of-kill profile similar to pyrimethamine in vitro and efficacy in the humanized P. falciparum Pf3D70087/N9 NODscidIL2Rγnull mouse model at a single dose of 25 mg/kg, with similar kinetics to chloroquine. Furthermore, compound 15 demonstrated significant transmission-blocking potential, achieving 90% inhibition of male gamete exflagellation, a 98% reduction in mean oocyst intensity, and an 88% block in transmission. Mechanism-of-action studies revealed that compound 15 disrupts Na+ ion homeostasis in P. falciparum, indicating that it functions as a PfATP4 inhibitor. However, due to the resistance risk associated with the PfATP4 target and the presence of more advanced clinical candidates, further development of 15 into a viable antimalarial drug is currently deprioritised.

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