2. Academic Validation
  3. Discovery and Optimization of Quinoline Analogues as Novel Potent Antivirals against Enterovirus D68

Discovery and Optimization of Quinoline Analogues as Novel Potent Antivirals against Enterovirus D68

  • J Med Chem. 2022 Nov 10;65(21):14792-14808. doi: 10.1021/acs.jmedchem.2c01311.
Xiaoyuan Li 1,  Yuexiang Li 1,  Shiyong Fan 1,  Ruiyuan Cao 1,  Xiaojia Li 1,  Xiaomeng He 1,  Wei Li 1,  Longfa Xu 2,  Tong Cheng 2,  Honglin Li 3,  Wu Zhong 1
Affiliations

Affiliations

  • 1 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, P.R. China.
  • 3 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, P.R. China.
PMID: 36254462 DOI: 10.1021/acs.jmedchem.2c01311
Abstract

Enterovirus D68 (EV-D68) is a nonpolio Enterovirus that is mainly transmitted through respiratory routes and poses a potential threat for large-scale spread. EV-D68 infections mostly cause moderate to severe respiratory diseases in children and potentially induce neurological diseases. However, there are no specific Antiviral drugs or vaccines against EV-D68. Herein, through virtual screening and rational design, a series of novel quinoline analogues as anti-EV-D68 agents targeting VP1 were identified. Particularly, 19 exhibited potent Antiviral activity with an EC50 value ranging from 0.05 to 0.10 μM against various EV-D68 strains and showed inhibition of viral replication verified by Western blot, immunofluorescence, and plaque formation assay. Mechanistic studies indicated that the anti-EV-D68 agents work mainly by interacting with VP1. The acceptable bioavailability of 23.9% in rats and significant metabolic stability in human liver microsome (Clint = 10.8 mL/min/kg, t1/2 = 148 min) indicated that compound 19 with a novel scaffold was worth further investigation.

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