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Updated: May 9, 2026
Arbovirus Infections As Screening Tools for the Identification of Viral Immunomodulators and Host Antiviral Factors
Published on: September 13, 2018
S5092 inhibit ASFV infection by targeting the pS273R protease activity in vitro
Chuanxia Liu1, Tingting Li1, Tao Huang2
1Division of Fundamental Immunology, National African Swine Fever Para-reference Laboratory, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Harbin 150069, China.
Abstract:
African Swine Fever (ASF) is a highly infectious viral disease caused by African swine fever virus (ASFV). Currently, there is no effective vaccine, and it is urgent to discover antiviral agents to deal with the epidemic. ASFV pS273R is the only known cysteine protease that catalyzes the maturation of the polyprotein precursors pp220 and pp62 through proteolytic cleavage, a critical step in ASFV assembly. In this study, we performed a high-throughput screening of an FDA-approved drug library to identify several compounds that target the active site of the ASFV pS273R enzyme via molecular docking. We initially identified 778 molecules based on the "Drug-like Five Principles", with S5092 emerging as the most promising candidate. S5092 is a prodrug that can be metabolized into Fenbendazole (FBZ) and Oxfendazole (OFZ). In exogenous cleavage experiments, S5092, FBZ, and OFZ significantly inhibited the cleavage of the viral polyprotein pp220 and pp62, as well as the host antiviral protein gasdermin D (GSDMD) by pS273R, indicating that these compounds inhibit the enzymatic activity of pS273R. Importantly, S5092 and its metabolites reduced the level of ASFV infection, as evidenced by the detection of viral genomic copies and viral titer. Collectively, our findings indicate that S5092 suppresses ASFV infection by inhibiting the enzyme activity of pS273R, a multifunction protein, positioning it as a novel and specific drug candidate for the prevention and control of ASF.
Insights
African Swine Fever (ASF) is a viral disease lacking vaccines. Researchers identified S5092, a drug metabolized to Fenbendazole and Oxfendazole, which inhibits the ASFV pS273R enzyme, reducing viral infection.
Area of Science:
- Veterinary Virology
- Drug Discovery
- Molecular Biology
Background:
- African Swine Fever (ASF) is a highly contagious viral disease caused by the African swine fever virus (ASFV).
- The absence of an effective vaccine necessitates the urgent discovery of antiviral agents.
- ASFV pS273R is a crucial cysteine protease involved in viral polyprotein maturation and ASFV assembly.
Purpose of the Study:
- To identify novel antiviral agents targeting the ASFV pS273R enzyme.
- To evaluate the efficacy of FDA-approved drugs against ASFV replication.
- To explore S5092 and its metabolites as potential therapeutic candidates for ASF.
Main Methods:
- High-throughput screening of an FDA-approved drug library using molecular docking.
- Identification of potential inhibitors targeting the ASFV pS273R active site.
- Exogenous cleavage assays to assess the inhibition of pS273R enzymatic activity on viral and host proteins.
Main Results:
- S5092 was identified as a promising drug candidate, metabolized into Fenbendazole (FBZ) and Oxfendazole (OFZ).
- S5092, FBZ, and OFZ demonstrated significant inhibition of pS273R's proteolytic cleavage activity on viral polyproteins (pp220, pp62) and GSDMD.
- Treatment with S5092 and its metabolites effectively reduced ASFV genomic copies and viral titer, indicating suppression of viral infection.
Conclusions:
- S5092 acts as a prodrug, with its metabolites FBZ and OFZ inhibiting the enzymatic activity of ASFV pS273R.
- The inhibition of pS273R by S5092 and its metabolites leads to a reduction in ASFV infection.
- S5092 represents a novel and specific drug candidate for the prevention and control of African Swine Fever.
