Small molecules targeting coxsackievirus A16 capsid inactivate viral particles and prevent viral binding

Abstract

Coxsackievirus A16 (CVA16) is an etiologic agent of hand, foot, and mouth disease (HFMD) that affects young children, and although typically self-limited, severe complications, and fatal cases have been reported. Due to the lack of specific medication and vaccines against CVA16, there is currently a need to develop effective antivirals to better control CVA16 infections in epidemic areas. In this study, we identified the tannins chebulagic acid (CHLA) and punicalagin (PUG) as small molecules that can efficiently disrupt the CVA16 infection of human rhabdomyosarcoma cells. Both compounds significantly reduced CVA16 infectivity at micromolar concentrations without apparent cytotoxicity. A mechanistic analysis revealed that the tannins particularly targeted the CVA16 entry phase by inactivating cell-free viral particles and inhibiting viral binding. Further examination by molecular docking analysis pinpointed the targets of the tannins in the fivefold axis canyon region of the CVA16 capsid near the pocket entrance that functions in cell surface receptor binding. We suggest that CHLA and PUG are efficient antagonists of CVA16 entry and could be of value as antiviral candidates or as starting points for developing molecules to treat CVA16 infections.

The Methanolic Extract of Perilla frutescens Robustly Restricts Ebola Virus Glycoprotein-Mediated Entry

“…Identifying antiviral agents that restrict EBOV entry into host cells and prevent establish-ment or limit propagation of its infection are advantageous as they could serve not only as therapeutic drugs, but also for prophylaxis purposes (pre-or post-exposure) which is key in reducing viral transmission and providing protection for high-risk healthcare workers [37]. Indeed, entry inhibitors have emerged as an important class of antiviral agents for the prevention/treatment of various viral infections and have been explored widely, including against HIV-1 [38][39][40][41], herpes simplex virus [28,42], avian influenza [43,44], dengue virus [45,46], hepatitis C virus [23,26,[47][48][49], measles virus [50,51], and enteroviruses [52,53]. These developments prove the utility and significance of entry inhibitors as a vital class of antiviral agents.…”

Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

“…For example, it inhibits the entry of herpes simplex virus 1 and other viruses by antagonizing the interactions of viral glycoprotein and cell-surface glycosaminoglycans [47][48][49][50]. It can also inhibit the viral NS3-4A protease of hepatitis C at low micromolar concentrations [33] and may also target the capsid protein of coxsackievirus A16 [51]. Notably, 1 mg/kg chebulagic acid also reduced mouse mortality following a lethal dose of human enterovirus 71, indicating that antiviral activity extends to in vivo models [52].…”

Field-Grown and In Vitro Propagated Round-Leaved Sundew (Drosera rotundifolia L.) Show Differences in Metabolic Profiles and Biological Activities

“…It is likely that this phenomenon is affected by the metabolic profile of the extracts. For example, Lin et al [20] found that polyphenols, such as tannins are effective against coxsackieviruses. None of the concentrations tested were cytotoxic (Figure 3C), which was evaluated using CPE Inhibition assay.…”

“…Tannins and other polyphenols have indeed been previously identified with antiviral activities. For example, Lin et al [20] found that tannins chebulagic acid and punicalagin significantly reduced the coxsackievirus infectivity by both inactivating cell-free viral particles and inhibiting viral binding. In another study by Du et al [33], resveratrolloaded nanoparticles were successful in inhibiting enterovirus replication and protecting rhabdosarcoma cells in vitro.…”