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

Alexandra S. Probst, Douglas G. Paton, Federico Appetecchia, Selina Bopp, Kelsey L. Adams, Tasneem A. Rinvee, Sovitj Pou, Rolf Winter, Esrah W. Du, Sabrina Yahiya, Charles Vidoudez, Naresh Singh, Janneth Rodrigues, Pablo Castañeda-Casado, Chiara Tammaro, Daisy Chen, Karla P. Godinez-Macias, Jasmine L. Jaramillo, Giovanna Poce, Michael J. Rubal, Aaron Nilsen, Elizabeth A. Winzeler, Jake Baum, Jeremy N. Burrows, Michael K. Riscoe, Dyann F. Wirth () and Flaminia Catteruccia ()
Additional contact information
Alexandra S. Probst: Harvard T. H. Chan School of Public Health
Douglas G. Paton: Harvard T. H. Chan School of Public Health
Federico Appetecchia: Harvard T. H. Chan School of Public Health
Selina Bopp: Harvard T. H. Chan School of Public Health
Kelsey L. Adams: Harvard T. H. Chan School of Public Health
Tasneem A. Rinvee: Harvard T. H. Chan School of Public Health
Sovitj Pou: VA Medical Center
Rolf Winter: VA Medical Center
Esrah W. Du: Harvard T. H. Chan School of Public Health
Sabrina Yahiya: Imperial College London
Charles Vidoudez: Harvard Center for Mass Spectrometry
Naresh Singh: Harvard T. H. Chan School of Public Health
Janneth Rodrigues: GlaxoSmithKline
Pablo Castañeda-Casado: GlaxoSmithKline
Chiara Tammaro: Sapienza University of Rome
Daisy Chen: University of California, San Diego
Karla P. Godinez-Macias: University of California, San Diego
Jasmine L. Jaramillo: Southwest Research Institute
Giovanna Poce: Sapienza University of Rome
Michael J. Rubal: Southwest Research Institute
Aaron Nilsen: VA Medical Center
Elizabeth A. Winzeler: University of California, San Diego
Jake Baum: Imperial College London
Jeremy N. Burrows: Medicines for Malaria Venture
Michael K. Riscoe: VA Medical Center
Dyann F. Wirth: Harvard T. H. Chan School of Public Health
Flaminia Catteruccia: Harvard T. H. Chan School of Public Health

Nature, 2025, vol. 643, issue 8072, 785-793

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09039-2

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