Paper Info
Title
Systematic optimization of host-directed therapeutic targets and preclinical validation of repositioned antiviral drugs
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.
Year
DOI
Venue
2022
10.1093/bib/bbac047
BRIEFINGS IN BIOINFORMATICS
Keywords
DocType
Volume
virus-host interactome, network analysis, drug target, drug repositioning, antiviral drugs
Journal
23
Issue
ISSN
Citations 
3
1467-5463
0
PageRank 
References 
Authors
0.34
0
10
Name
Order
Citations
PageRank
Dafei Xie100.68
Song He253.78
Lu Han300.34
Lianlian Wu400.34
Hai Huang500.34
Huan Tao601.35
Pingkun Zhou7101.33
Xunlong Shi800.34
Hui Bai900.34
Xiaochen Bo1028523.72