Systematic Optimization of Host-Directed Therapeutic Targets and Preclinical Validation of Repositioned Antiviral Drugs

Host-targeting strategies can reduce the emergence of viral resistance, and drug repositioning can shorten the drug development cycle, reduce costs, and mitigate safety-related risks. Therefore, the host-targeting antiviral drug repositioning strategy can provide a new and effective approach for the prevention, control, and treatment of viral infectious diseases.GenomicsThe extensive host protein data accumulated from research has provided a large number of candidate genes for antiviral drug target identification. There is now an urgent need for comprehensive evaluation and systematic optimization of virus-targeted host proteins (VTHP) and drug targets.

Recently, the Bo Xiaochen team from the Academy of Military Medical Sciences, in collaboration with the Shi Xunlong team from Fudan University and the Bai Hui team from BioMap, published a research paper titled "Systematic optimization of host-directed therapeutic targets and preclinical validation of repositioned antiviral drugs" in the journal Briefings in Bioinformatics.

The study classified virus infection patterns based on the enrichment analysis of virus-targeted host protein (VTHP) pathways, revealing that non-essential membrane and/or hub proteins are the most ideal potential antiviral repositioning drug targets. Furthermore, based on the drug-virus network (DVN), it reviewed the possibility of known drugs being repurposed for host-targeting antiviral applications, and conducted preclinical evaluation and validation of three predicted drugs through cellular and animal experiments.

This study, based on the full integration of the known 6,140 VTHPs, classified the infection patterns of 35 viruses from the novel perspective of pathway enrichment:

1) Cancer Pathway Unrelated Viruses (CPUV) 10 types;

2) Protein metabolism-related viruses (PMRV) 3 types;

3) Cell Cycle and Apoptosis-Related Viruses (CARV) 10 types;

4) Other carcinogenic pathway-related viruses (OCPRV) 12 types (Figure 1).

Subsequently, we identified the most promising criteria for screening antiviral repositioning drug targets as: druggable, non-EGEP, membrane and/or hub proteins, and proposed 543 ideal candidate targets. Based on this, we constructed a Drug-Virus Network (DVN) using shared targets and found that among the known drugs repositioned for antiviral applications, neurological drugs were the most common, followed by gastrointestinal and metabolic drugs. Through the DVN, we further predicted 703 approved drugs that could potentially be repositioned for treating 35 viral infections and analyzed their broad-spectrum antiviral potential (Figure 2).

We confirmed the activity of Bosutinib against Human Herpesvirus 1 (HHV-1), Maraviroc against Hepatitis B Virus (HBV), and Dextromethorphan against Influenza A Virus (IAV) through cellular and animal experiments, and evaluated their combined effects with virus-targeting drugs currently used in clinical practice.

For HHV-1, within the non-toxic concentration range, bosutinib significantly inhibits CPE with the highest therapeutic coefficient. However, when combined with acyclovir used clinically, it exhibits drug antagonism across a wide concentration range (Figure 3).

Among the predicted anti-HBV repositioned drugs, Maraviroc demonstrated the strongest inhibitory effect on HBsAg secretion and the highest therapeutic index within the non-toxic concentration range. The combination of Maraviroc and Lamivudine, a clinically used drug, showed drug synergy only within a limited specific concentration range (Figure 4).

For IAV, in cellular experiments, the IC50 of dextromethorphan within the non-toxic concentration range was 22.2 μg/ml. Its combination with oseltamivir, clinically used, demonstrated drug synergy in both short-term high-dose and long-term low-dose infection models. In animal experiments, we found that dextromethorphan + oseltamivir effectively reduced lung injury caused by viral infection, improved pathological changes, and extended the survival time of mice. Whether used alone or in combination, a low dose concentration (15 mg/kg/d) of dextromethorphan showed better efficacy (Figure 5).BioValleyBioon.com）