2. Academic Validation
  3. In vivo screen of Plasmodium targets for mosquito-based malaria control

In vivo screen of Plasmodium targets for mosquito-based malaria control

  • Nature. 2025 May 21. doi: 10.1038/s41586-025-09039-2.
Alexandra S Probst # 1,  Douglas G Paton # 1 2,  Federico Appetecchia 1,  Selina Bopp 1,  Kelsey L Adams 1,  Tasneem A Rinvee 1,  Sovitj Pou 3,  Rolf Winter 3,  Esrah W Du 1,  Sabrina Yahiya 4,  Charles Vidoudez 5,  Naresh Singh 1,  Janneth Rodrigues 6,  Pablo Castañeda-Casado 6,  Chiara Tammaro 7,  Daisy Chen 8,  Karla P Godinez-Macias 8,  Jasmine L Jaramillo 9,  Giovanna Poce 7,  Michael J Rubal 9,  Aaron Nilsen 3 10,  Elizabeth A Winzeler 8,  Jake Baum 4 11,  Jeremy N Burrows 12,  Michael K Riscoe 3 10,  Dyann F Wirth 13 14,  Flaminia Catteruccia 15 16
Affiliations

Affiliations

  • 1 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • 2 Department of Infectious Disease, University of Georgia, Athens, GA, USA.
  • 3 VA Medical Center, Portland, OR, USA.
  • 4 Department of Life Sciences, Imperial College London, London, UK.
  • 5 Harvard Center for Mass Spectrometry, Cambridge, MA, USA.
  • 6 Global Health Medicines R&D, GlaxoSmithKline, Madrid, Spain.
  • 7 Department of Chemistry and Pharmaceutical Technologies, Sapienza University of Rome, Rome, Italy.
  • 8 Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • 9 Southwest Research Institute, San Antonio, TX, USA.
  • 10 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
  • 11 School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
  • 12 Medicines for Malaria Venture, Geneva, Switzerland.
  • 13 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. dfwirth@hsph.harvard.edu.
  • 14 Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA, USA. dfwirth@hsph.harvard.edu.
  • 15 Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. fcatter@hsph.harvard.edu.
  • 16 Howard Hughes Medical Institute, Boston, MA, USA. fcatter@hsph.harvard.edu.
  • # Contributed equally.
PMID: 40399670 DOI: 10.1038/s41586-025-09039-2
Abstract

The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)1,2. One way to mitigate Insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs. This strategy can prevent onward Parasite transmission even when insecticides lose efficacy3,4. Here, we performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development. Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early Parasite stages in the mosquito midgut lumen, which in turn prevented establishment of Infection. Medicinal chemistry was then used to improve antiparasitic activity of the top hits from the screen. We generated several endochin-like quinolones (ELQs) that inhibited the P. falciparum cytochrome bc1 complex (CytB). Two lead compounds that targeted separate sites in CytB (Qo and Qi) showed potent, long-lasting and stable activity when incorporated and/or extruded into bed net-like polyethylene films. ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage. These data demonstrate the promise of incorporating ELQ compounds into LLINs to counteract Insecticide resistance and to reduce malaria transmission.

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