2. Academic Validation
  3. CX-6258 hydrochloride hydrate: A potential non-nucleoside inhibitor targeting the RNA-dependent RNA polymerase of norovirus

CX-6258 hydrochloride hydrate: A potential non-nucleoside inhibitor targeting the RNA-dependent RNA polymerase of norovirus

  • Virology. 2024 Apr 17:595:110088. doi: 10.1016/j.virol.2024.110088.
Yang Liu 1,  Quanjie Li 2,  Huihan Shao 3,  Yang Mao 4,  Lufei Liu 3,  Dongrong Yi 3,  Zhaojun Duan 5,  Huiqing Lv 6,  Shan Cen 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: quanjie.li@imb.pumc.edu.cn.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 4 Ningbo Prefectural Center for Disease Control and Prevention, Ningbo, 315010, China.
  • 5 Institute for Viral Disease Control & Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
  • 6 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China. Electronic address: lvhuiqing@zcmu.edu.cn.
  • 7 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; CAMS Key Laboratory of Antiviral Drug Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China. Electronic address: shancen@imb.pumc.edu.cn.
PMID: 38643657 DOI: 10.1016/j.virol.2024.110088
Abstract

Human norovirus (HuNoV), a primary cause of non-bacterial gastroenteritis, currently lacks approved treatment. RdRp is vital for virus replication, making it an attractive target for therapeutic intervention. By application of structure-based virtual screening procedure, we present CX-6258 hydrochloride hydrate as a potent RdRp non-nucleoside inhibitor, effectively inhibiting HuNoV RdRp activity with an IC50 of 3.61 μM. Importantly, this compound inhibits viral replication in Cell Culture, with an EC50 of 0.88 μM. In vitro binding assay validate that CX-6258 hydrochloride hydrate binds to RdRp through interaction with the "B-site" binding pocket. Interestingly, CX-6258-contacting residues such as R392, Q439, and Q414 are highly conserved among major norovirus GI and GII variants, suggesting that it may be a general inhibitor of norovirus RdRp. Given that CX-6258 hydrochloride hydrate is already utilized as an orally efficacious pan-Pim kinase inhibitor, it may serve as a potential lead compound in the effort to control HuNoV infections.

Keywords

CX-6258 hydrochloride hydrate; Non-nucleoside inhibitor; Norovirus; RdRp; Virtual screening.

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