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.
| Original language | English |
|---|---|
| Article number | eadq1383 |
| Pages (from-to) | 1-19 |
| Journal | Science advances |
| Volume | 10 |
| Issue number | 49 |
| Early online date | 6 Dec 2024 |
| DOIs | |
| Publication status | Published - 6 Dec 2024 |
Bibliographical note
Publisher Copyright:Copyright © 2024 The Authors, some rights reserved
Funding
We would like to thank G. Henriques for training staff in handling P. falciparum. We are grateful to M. Blackman (Francis Crick Institute) and A. Bell (Salvensis) for discussions on aspects of this work. We would like to thank the CRO synthetic chemists and drug discovery biologists at TCG-LS for making the compounds used in this study and performing key assays. We would also like to thank E. Chenu and D. Baud at MMV for logistical support during the project. We are grateful to W. Chen (MSc placement student from University College, London) for assistance with initial screening of compounds for activity against Plasmodium PDE activity. We are grateful to C. Sutherland for facilitating the SMFA experiments carried out in the Human Malaria Transmission Facility at LSHTM. We would like to thank M. Noe from Pfizer for helping arrange the release of information and compounds to LSHTM and also J. Warmus, M. Troutman, J. Mills, and I. Reza for arranging to have ADME properties tested on selected compounds at Pfizer. We are grateful to the Wellcome Trust for Innovator (209367/Z/17/Z and 223849/Z/21/Z) and Investigator Awards (106240/Z/14/Z and 220318/Z/20/Z) to D.A.B. and the Biomedical Resources Grant (221363/Z/20/Z) that supports the Human Malaria Transmission Facility at LSHTM. Resistance selection studies and research on Ugandan parasites were supported in part by the US National Institutes of Health (R01 AI185559 to D.A.F., R01 AI1075045 and R01 AI139179 to P.J.R., and K08AI163497 to J.L.S.-S.) and the Bill & Melinda Gates Foundation (INV-033538 to D.A.F.). D.A.F., D.A.B., L.-M.B., and P.J.R. also acknowledge support from the Medicines for Malaria Venture. Acknowledgments: We would like to thank G. henriques for training staff in handling P. falciparum. We are grateful to M. Blackman (Francis crick institute) and A. Bell (Salvensis) for discussions on aspects of this work. We would like to thank the cRO synthetic chemists and drug discovery biologists at tcG-lS for making the compounds used in this study and performing key assays. We would also like to thank e. chenu and D. Baud at MMv for logistical support during the project. We are grateful to W. chen (MSc placement student from University college, london) for assistance with initial screening of compounds for activity against Plasmodium PDe activity. We are grateful to c. Sutherland for facilitating the SMFA experiments carried out in the human Malaria transmission Facility at lShtM. We would like to thank M. noe from Pfizer for helping arrange the release of information and compounds to lShtM and also J. Warmus, M. troutman, J. Mills, and i. Reza for arranging to have ADMe properties tested on selected compounds at Pfizer. Funding: We are grateful to the Wellcome trust for innovator (209367/Z/17/Z and 223849/Z/21/Z) and investigator Awards (106240/Z/14/Z and 220318/Z/20/Z) to D.A.B. and the Biomedical Resources Grant (221363/Z/20/Z) that supports the human Malaria transmission Facility at lShtM. Resistance selection studies and research on Ugandan parasites were supported in part by the US national institutes of health (R01 Ai185559 to D.A.F., R01 Ai1075045 and R01 Ai139179 to P.J.R., and K08Ai163497 to J.l.S.-S.) and the Bill & Melinda Gates Foundation (inv-033538 to D.A.F.).
| Funders | Funder number |
|---|---|
| London School of Hygiene and Tropical Medicine | |
| Human Malaria Transmission Facility | |
| Medicines for Malaria Venture | |
| University College | |
| Pfizer | |
| National Institutes of Health | R01 Ai139179, K08Ai163497, R01 Ai185559, R01 Ai1075045 |
| Wellcome Trust for Innovator | 106240/Z/14/Z, 209367/Z/17/Z, 221363/Z/20/Z, 220318/Z/20/Z, 223849/Z/21/Z |
| Bill and Melinda Gates Foundation | INV-033538 |
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