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

Weining Sun; Ziling Zhang; Mingxin Chen; Xinlei Liu; Yifei Wang; Shaohua Yao; Linli Li

doi:10.1016/j.bbrc.2023.08.027

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

Biochem Biophys Res Commun. 2023 Oct 20:678:97-101. doi: 10.1016/j.bbrc.2023.08.027. Epub 2023 Aug 12.

Authors

Weining Sun¹, Ziling Zhang², Mingxin Chen¹, Xinlei Liu¹, Yifei Wang¹, Shaohua Yao¹, Linli Li³

Affiliations

¹ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
³ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: lilinli@scu.edu.cn.

PMID: 37625270
DOI: 10.1016/j.bbrc.2023.08.027

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 K_D 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.

Keywords: Crystal complex structure; Influenza A virus; PB2; Small molecule inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

RNA-Dependent RNA Polymerase