Abstract
Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.
Highlights
Since the earliest yellow fever virus was discovered in 1901, the number of viruses has continued to increase
Coronavirus disease (COVID-19) caused by SARS-CoV-2 has led to a global pandemic and can result in a series of respiratory diseases, such as pneumonia and lung failure [2,3,4]; Ebola virus causes a range of highly pathogenic symptoms, such as hemorrhagic fever, and is highly contagious, with a mortality rate of 57%–90% [5]; Severe Acute Respiratory Syndrome (SARS), has affected more than 8000 people and killed 774 people by July 2003 [6]; Epstein-Barr virus (EBV), a common human herpes DNA virus, can lead to lifelong infection in more than 90 percent of the population, and causes a variety of human malignancies [7]; Human
The challenge for antiviral drug discovery arises from the mutation and drug-resistance of viruses
Summary
Since the earliest yellow fever virus was discovered in 1901, the number of viruses has continued to increase. A large number of gene loci related to susceptibility to viral diseases (such as HIV, hepatitis, dengue (DEN) etc.) have been discovered by genome-wide association studies (GWAS) [32]. These results further elucidate the genetic structure of susceptibility to infectious diseases. Tyrrell et al selected the endoplasmic reticulum a-glucosidases as a target based on the glycosylation mechanism, and iminosugars were shown to have potential efficacy in difficult-to-treat infections [37] Up to now, this strategy has been successful in the treatment of DEN [38] and other viral diseases [39,40,41]. Based on the summarized features, potential host-aimed antiviral targets were screened, in an attempt to promote the development of new antiviral drugs
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