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
  • 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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