2. Academic Validation
  3. Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission

  • Sci Adv. 2024 Dec 6;10(49):eadq1383. doi: 10.1126/sciadv.adq1383.
Paula-Josefina Gomez-Gonzalez 1,  Antima Gupta 1,  Laura G Drought 1,  Avnish Patel 1,  John Okombo 2 3,  Mariëtte van der Watt 4,  Ryan Walker-Gray 1,  Kyra A Schindler 2 3,  Anna Y Burkhard 2 3,  Tomas Yeo 2 3,  Sunil K Narwal 2 3,  Talia S Bloxham 3 5,  Christian Flueck 1,  Eloise M Walker 1,  Joshua A Rey 1,  Kate J Fairhurst 2 3,  Janette Reader 4 6,  Heekuk Park 3 5,  Harry G Pollard 1,  Lindsay B Stewart 1,  Luke Brandner-Garrod 1,  Mojca Kristan 1,  Geert-Jan Sterk 7,  Youri M van Nuland 8,  Emilia Manko 1,  Donelly A van Schalkwyk 1,  Yang Zheng 7,  Rob Leurs 7,  Koen J Dechering 8,  Anna Caroline C Aguiar 9,  Rafael V C Guido 10,  Dhelio B Pereira 11,  Patrick K Tumwebaze 12,  Samuel L Nosbya 12,  Philip J Rosenthal 13,  Roland A Cooper 14,  Mike Palmer 15,  Tanya Parkinson 15,  Jeremy N Burrows 16 17,  Anne-Catrin Uhlemann 3 5,  Lyn-Marié Birkholtz 4 6,  Jennifer L Small-Saunders 3 5,  James Duffy 16,  David A Fidock 2 3 5,  Alan Brown 15,  Mark Gardner 15,  David A Baker 1
Affiliations

Affiliations

  • 1 Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
  • 2 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 3 Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa.
  • 5 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 6 Institute for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa.
  • 7 Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • 8 TropIQ Health Sciences, Nijmegen, Netherlands.
  • 9 Federal University of São Paulo, São Paulo, Brazil.
  • 10 Sao Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil.
  • 11 Research Center for Tropical Medicine of Rondonia, Porto Velho, Brazil.
  • 12 Infectious Diseases Research Collaboration, Kampala, Uganda.
  • 13 University of California, San Francisco, CA, USA.
  • 14 Dominican University of California, San Rafael, CA, USA.
  • 15 Salvensis, Sandwich, UK.
  • 16 Medicines for Malaria Venture, Geneva, Switzerland.
  • 17 Liverpool School of Tropical Medicine, Liverpool, UK.
PMID: 39642214 DOI: 10.1126/sciadv.adq1383
Abstract

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria Parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent Plasmodium falciparum PDEβ inhibitors that block asexual blood-stage Parasite development and that are also active against human clinical isolates. Two of the inhibitor subseries also have potent transmission-blocking activity by targeting PDEs expressed during sexual Parasite development. In vitro drug selection experiments generated parasites with moderately reduced susceptibility to the inhibitors. Whole-genome Sequencing of these parasites detected no mutations in PDEβ but rather mutations in downstream effectors: either the catalytic or regulatory subunits of cyclic adenosine monophosphate-dependent protein kinase (PKA) or in the 3-phosphoinositide-dependent protein kinase that is required for PKA activation. Several properties of these P. falciparum PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.

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