Discovery of a potent inhibitor targeting the cap-binding domain of the PB2 subunit of influenza RNA-dependent RNA polymerase.

Abstract

Influenza pandemics have emerged as a significant global public health and security concern. PB2, a crucial subunit of the influenza RNA-dependent RNA polymerase (RdRP), has been identified as a promising target for influenza treatment. We herein report the discovery of a potent novel PB2 inhibitor, 7-51A, with a KD value of 1.64 nM as determined by ITC. The high activity of 7-51A was elucidated by the co-crystal structure of the PB2-7-51A complex, and comparative analysis revealed unique interactions that had never been observed before. The preliminary pharmacological evaluation indicated that 7-51A exhibited commendable cellular safety, hepatic microsomal metabolic safety and stability. Collectively, 7-51A was found to be an effective PB2 inhibitor and could be used as a lead compound for further studies.

• Authors: Weining Sun, Ziling Zhang, Mingxin Chen, Xinlei Liu, Yifei Wang, Shaohua Yao, Linli Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 678 Pg. 97-101 (10 20 2023) ISSN: 1090-2104 [Electronic] United States
• PMID: 37625270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• RNA-Dependent RNA Polymerase

Topics

• Humans
• Influenza, Human
• Pandemics
• Public Health
• RNA-Dependent RNA Polymerase