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Viruses. 2019 Sep 5;11(9). pii: E826. doi: 10.3390/v11090826.

A Parallel Phenotypic Versus Target-Based Screening Strategy for RNA-Dependent RNA Polymerase Inhibitors of the Influenza A Virus.

Zhao X1, Wang Y2, Cui Q3,4,5, Li P6, Wang L7, Chen Z8, Rong L9, Du R10,11,12.

Author information

1
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. xiujuan95@163.com.
2
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
3
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. cuiqinghua1122@163.com.
4
Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan 250355, China. cuiqinghua1122@163.com.
5
Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China. cuiqinghua1122@163.com.
6
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. liping9309@163.com.
7
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. lynn942@163.com.
8
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. chenzinuo96@163.com.
9
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. lijun@uic.edu.
10
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. duzi857@163.com.
11
Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan 250355, China. duzi857@163.com.
12
Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China. duzi857@163.com.

Abstract

Influenza A virus infections cause significant morbidity and mortality, and novel antivirals are urgently needed. Influenza RNA-dependent RNA polymerase (RdRp) activity has been acknowledged as a promising target for novel antivirals. In this study, a phenotypic versus target-based screening strategy was established to identify the influenza A virus inhibitors targeting the virus RNA transcription/replication steps by sequentially using an RdRp-targeted screen and a replication-competent reporter virus-based approach using the same compounds. To demonstrate the utility of this approach, a pilot screen of a library of 891 compounds derived from natural products was carried out. Quality control analysis indicates that the primary screen was robust for identification of influenza A virus inhibitors targeting RdRp activity. Finally, two hit candidates were identified, and one was validated as a putative RdRp inhibitor. This strategy can greatly reduce the number of false positives and improve the accuracy and efficacy of primary screening, thereby providing a powerful tool for antiviral discovery.

KEYWORDS:

Influenza A virus; RNA dependent RNA polymerase inhibitor; phenotypic screen; target-based screen

PMID:
31491939
DOI:
10.3390/v11090826
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