Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission
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 <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.
Authors
- Roland A. Cooper (ORCID: https://orcid.org/0000-0002-8437-9382)
- Koen J. Dechering (ORCID: https://orcid.org/0000-0002-8124-4634)
- Paula Josefina Gómez (ORCID: https://orcid.org/0000-0002-3670-8786)
- Luke Brandner-Garrod
- Mark Palmer (ORCID: https://orcid.org/0000-0002-9183-0696)
- Lindsay B. Stewart (ORCID: https://orcid.org/0000-0002-9003-0160)
- Mark Gardner (ORCID: https://orcid.org/0000-0002-9322-1181)
- John Okombo (ORCID: https://orcid.org/0000-0001-8680-2351)
- Youri M. van Nuland (ORCID: https://orcid.org/0000-0002-2481-2754)
- Alan Brown (ORCID: https://orcid.org/0000-0002-1936-6315)
- Anna Y. Burkhard
- Kyra A. Schindler (ORCID: https://orcid.org/0000-0002-4406-9160)
- Kate J. Fairhurst
- Heekuk Park (ORCID: https://orcid.org/0000-0001-5815-9717)
- Mojca Kristan (ORCID: https://orcid.org/0000-0002-0363-8558)
- Christian Flueck (ORCID: https://orcid.org/0000-0001-9145-9324)
- Jennifer L. Small-Saunders (ORCID: https://orcid.org/0000-0001-6064-2249)
- Tanya Parkinson
- Dhélio B. Pereira (ORCID: https://orcid.org/0000-0002-7761-5498)
- Janette Reader (ORCID: https://orcid.org/0000-0001-9026-0583)
- Tomas Yeo (ORCID: https://orcid.org/0000-0003-2923-6060)
- Donelly A. van Schalkwyk (ORCID: https://orcid.org/0000-0002-7375-3439)
- Yang Zheng (ORCID: https://orcid.org/0000-0001-7035-8807)
- Anna Caroline Campos Aguiar (ORCID: https://orcid.org/0000-0003-0139-8279)
- Emilia Mańko (ORCID: https://orcid.org/0000-0001-7405-6523)
- Eloise M. Walker (ORCID: https://orcid.org/0000-0003-3132-8861)
- Anumeha Gupta
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Sunil Kumar Narwal (ORCID: https://orcid.org/0000-0001-5476-9753)
- James Duffy (ORCID: https://orcid.org/0000-0002-9447-8982)
- Mariëtte van der Watt (ORCID: https://orcid.org/0000-0002-9933-8647)
- Philip J. Rosenthal (ORCID: https://orcid.org/0000-0002-7953-7622)
- Patrick K. Tumwebaze (ORCID: https://orcid.org/0000-0002-5933-1432)
- Rafael V. C. Guido (ORCID: https://orcid.org/0000-0002-7187-0818)
- David A. Baker (ORCID: https://orcid.org/0000-0002-5490-8933)
- Lyn‐Marié Birkholtz (ORCID: https://orcid.org/0000-0001-5888-2905)
- Laura Drought (ORCID: https://orcid.org/0000-0002-6290-5900)
- Rob Leurs (ORCID: https://orcid.org/0000-0003-1354-2848)
- Jeremy N. Burrows (ORCID: https://orcid.org/0000-0001-8448-6068)
- Anne‐Catrin Uhlemann (ORCID: https://orcid.org/0000-0002-9798-4768)
- Talia S. Bloxham (ORCID: https://orcid.org/0009-0002-8613-0457)
- Avnish Patel (ORCID: https://orcid.org/0000-0002-3608-3405)
- Geert-Jan Sterk
- Harry Pollard
- Joshua A. Rey
- Samuel L. Nosbya
- Ryan Walker-Gray
Institutions
- Dominican University of California (US)
- Universidade de São Paulo (BR)
- University of California, San Francisco (US)
- Liverpool School of Tropical Medicine (GB)
- Columbia University Irving Medical Center (US)
- London School of Hygiene & Tropical Medicine (GB)
- Infectious Diseases Research Collaboration (UG)
- TropIQ Health Sciences (NL)
- The Research Network (GB)
- Medicines for Malaria Venture (CH)
- University of Pretoria (ZA)
- Vrije Universiteit Amsterdam (NL)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1126/sciadv.adq1383
- Citations
- 3
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Francis Crick Institute