A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites

• Authors: SP Maher, University of Georgia; MA Bakowski, Calibr, a division of The Scripps Research Institute; La Jolla; A Vantaux, Institute Pasteur of Cambodia; EL Flannery, Novartis Institutes for Biomedical Research; C Andolina, Mahidol-Oxford Tropical Medicine Research Unit; M Gupta, University of California; Riverside; Y Antonova-Koch, Calibr, a division of The Scripps Research Institute; La Jolla; M Argomaniz, University of Georgia; Athens; M Cabrera-Mora, Emory University; B Campo, Medicines for Malaria Venture (MMV); Geneva, 1215, Switzerland.; AT Chao, Novartis Institutes for Biomedical Research; AK Chatterjee, Calibr, a division of The Scripps Research Institute; La Jolla, CA; WT Cheng, University of Georgia; Athens; CA Cooper, University of Georgia; Athens; K Cottier, BioIVT Inc.; Westbury, NY, 11590, USA.; Mary Galinski, Emory University; A Harupa-Chung, Novartis Institutes for Biomedical Research; H Ji, University of Georgia; Athens; SB Joseph, Calibr, a division of The Scripps Research Institute; La Jolla, CA,; T Lenz, University of California; Riverside; S Lonardi, University of California; Riverside; J Matheson, University of Otago; SA Mikolajczak, Novartis Institutes for Biomedical Research; V Padin-Irizarry, University of Georgia; Athens; K Pan, Calibr, a division of The Scripps Research Institute; La Jolla, CA; J Peneau, Institute Pasteur of Cambodia; Phnom Penh; J Prudhomme, University of California; Riverside; C Roesch, Institute Pasteur of Cambodia; Phnom Penh; AA Ruberto, University of Georgia; Athens; SS Sabnis, University of Georgia; Athens; CL Saney, University of Georgia; Athens; J Sattabongkot, Mahidol University; Bangkok; S Sereshki, University of California; S Suriyakan, Mahidol-Oxford Tropical Medicine Research Unit; T Moeller, BioIVT Inc.; Westbury, NY, 11590; R Ubalee, Armed Forces Research Institute of Medical Sciences (AFRIMS); Bangkok; Y Wang, University of California; P Wasisakun, Mahidol-Oxford Tropical Medicine Research Unit; J Yin, University of California; Riverside; CW McNamara, Calibr, a division of The Scripps Research Institute; La Jolla; C J Joyner, University of Georgia; Athens; F Nosten, Mahidol-Oxford Tropical Medicine Research Unit; B Witkowski, Institute Pasteur of Cambodia; Phnom Penh, 120 210, Cambodia.; KG Le Roch, University of California; Riverside; DE Kyle, University of Georgia; Athens
• Journal Title: bioRxiv
• Volume: Volume 2023
• Publisher: NIH | 2023-06-19
• Type of Work: Article | Preprint: Prior to Peer Review
• Publisher DOI: http://doi.org/10.1101/2023.01.31.526483
• Subjects: Health Sciences, Epidemiology
• Keywords: Plasmodium vivax Hypnozoites

Abstract

Radical cure of Plasmodium vivax malaria must include elimination of quiescent "hypnozoite" forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.