Systematic optimization of host-directed therapeutic targets and preclinical validation of repositioned antiviral drugs

Author:

Xie Dafei1,He Song1ORCID,Han Lu2,Wu Lianlian3ORCID,Huang Hai4,Tao Huan1,Zhou Pingkun1,Shi Xunlong4,Bai Hui5,Bo Xiaochen1ORCID

Affiliation:

1. Beijing Institute of Radiation Medicine, Beijing, China, 100850

2. Beijing Institute of Pharmacology and Toxicology, Beijing, China, 100850

3. Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China, 300072

4. Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China, 201203

5. BioMap (Beijing) Intelligence Technology Limited, Beijing, China, 100005

Abstract

Abstract Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant variants and favorable balance of costs and risks. Genomic methods have produced a large number of robust host factors, providing candidates for identification of antiviral drug targets. However, there is a lack of global perspectives and systematic prioritization of known virus-targeted host proteins (VTHPs) and drug targets. There is also a need for host-directed repositioned antivirals. Here, we integrated 6140 VTHPs and grouped viral infection modes from a new perspective of enriched pathways of VTHPs. Clarifying the superiority of nonessential membrane and hub VTHPs as potential ideal targets for repositioned antivirals, we proposed 543 candidate VTHPs. We then presented a large-scale drug–virus network (DVN) based on matching these VTHPs and drug targets. We predicted possible indications for 703 approved drugs against 35 viruses and explored their potential as broad-spectrum antivirals. In vitro and in vivo tests validated the efficacy of bosutinib, maraviroc and dextromethorphan against human herpesvirus 1 (HHV-1), hepatitis B virus (HBV) and influenza A virus (IAV). Their drug synergy with clinically used antivirals was evaluated and confirmed. The results proved that low-dose dextromethorphan is better than high-dose in both single and combined treatments. This study provides a comprehensive landscape and optimization strategy for druggable VTHPs, constructing an innovative and potent pipeline to discover novel antiviral host proteins and repositioned drugs, which may facilitate their delivery to clinical application in translational medicine to combat fatal and spreading viral infections.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Information Systems

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