- Main
A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.
- Maher, Steven P;
- Bakowski, Malina A;
- Vantaux, Amelie;
- Flannery, Erika L;
- Andolina, Chiara;
- Gupta, Mohit;
- Antonova-Koch, Yevgeniya;
- Argomaniz, Magdalena;
- Monica, Cabrera-Mora;
- Brice, Campo;
- Chao, Alexander T;
- Chatterjee, Arnab K;
- Cheng, Wayne T;
- Cooper, Caitlin A;
- Karissa, Cottier;
- Galinski, Mary R;
- Harupa-Chung, Anke;
- Ji, Hana;
- Joseph, Sean B;
- Lenz, Todd;
- Lonardi, Stefano;
- Matheson, Jessica;
- Mikolajczak, Sebastian A;
- Padin-Irizarry, Vivian;
- Pan, Kastin;
- Peneau, Julie;
- Prudhomme, Jacques;
- Roesch, Camille;
- Ruberto, Anthony A;
- Sabnis, Saniya S;
- Saney, Celia L;
- Sattabongkot, Jetsumon;
- Sereshki, Saleh;
- Suriyakan, Sangrawee;
- Timothy, Moeller;
- Ubalee, Ratawan;
- Wang, Yinsheng;
- Wasisakun, Praphan;
- Yin, Jiekai;
- McNamara, Case W;
- Joyner, Chester J;
- Nosten, Francois;
- Witkowski, Benoit;
- Le Roch, Karine G;
- Kyle, Dennis E
- et al.
Published Web Location
https://doi.org/10.1101/2023.01.31.526483Abstract
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.
Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
Main Content
Enter the password to open this PDF file:
-
-
-
-
-
-
-
-
-
-
-
-
-
-