An orally available PfPKG inhibitor blocks Plasmodium's infection of the liver

Authors

• Hanna Dhiyebi, Rutgers New Jersey Medical School
• Aminata Mbaye, Rutgers New Jersey Medical School
• Anusha Thaniana, Rutgers New Jersey Medical School
• John Gilleran, Rutgers University
• Tyler Eck, Montclair State UniversityFollow
• Kutub Ashraf, Walter Reed Army Institute of Research
• Karl Kudyba, Walter Reed Army Institute of Research
• Howard Fan, Rutgers New Jersey Medical School
• Steve Seibold, Seattle Children's Center for Global infectious Disease Research
• Kevin P. Battaile, New York Structural Biology Center
• John Siekierka, Montclair State University
• Evan Johnson, Rutgers New Jersey Medical School
• Alison Roth, Walter Reed Army Institute of Research
• Amy De Rocher, Seattle Children's Center for Global infectious Disease Research
• Scott Lovell, Seattle Children's Center for Global infectious Disease Research
• Edward B. Miller, Schrödinger, Inc.
• Jacques Y. Roberge, Rutgers University
• Purnima Bhanot, Rutgers New Jersey Medical School

Document Type

Article

Publication Date

7-1-2026

Journal / Book Title

PLoS Pathogens

Abstract

Malaria remains a global health threat exacerbated by emerging resistance to antimalarial therapies and insecticides, climate-driven outbreaks, and limited chemoprotective options. Here, we report the characterization of RUPB-61, the first orally bioavailable inhibitor of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG). RUPB-61 prevents infection by P. falciparum and P. cynomolgi sporozoites, including the formation of hypnozoites by the latter. A single oral dose blocks liver infection by P. berghei sporozoites in vivo, demonstrating efficacy consistent with further development as a once-weekly prophylaxis based on pharmacokinetic modeling. The compound retains activity against field isolates resistant to chloroquine, mefloquine, cycloguanil, sulfadoxine and pyrimethamine, suggesting low likelihood of cross-resistance to existing antimalarials. Structural studies and free energy-based modeling guided-compound design prospectively validated the predictive accuracy of an in silico model of PfPKG interactions with this chemotype. While selectivity profiling identified off-target activity against human kinases, structural modeling provides a clear path for optimization. These results establish PfPKG inhibitors as promising candidates for chemoprevention and support further preclinical development of the RUPB-61 chemotype.

DOI

10.1371/journal.ppat.1014322

Montclair State University Digital Commons Citation

Dhiyebi, Hanna; Mbaye, Aminata; Thaniana, Anusha; Gilleran, John; Eck, Tyler; Ashraf, Kutub; Kudyba, Karl; Fan, Howard; Seibold, Steve; Battaile, Kevin P.; Siekierka, John; Johnson, Evan; Roth, Alison; De Rocher, Amy; Lovell, Scott; Miller, Edward B.; Roberge, Jacques Y.; and Bhanot, Purnima, "An orally available PfPKG inhibitor blocks Plasmodium's infection of the liver" (2026). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 668.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/668

Published Citation

Dhiyebi, H., Mbaye, A., Thaniana, A., Gilleran, J., Eck, T., Ashraf, K., ... & Bhanot, P. (2026). An orally available PfPKG inhibitor blocks Plasmodium’s infection of the liver. PLoS pathogens, 22(7), e1014322.