Bothropstoxins I and II as potent phospholipase A2 molecules from Bothrops jararacussu to impair hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) (now classified Hepacivirus hominis) that infects an estimated 50 million individuals worldwide and causes chronic liver disease. The current treatment for infected patients primarily relies on direct-acting antivirals (DAAs). However, this treatment is marked by its high cost, numerous side effects, and documented instances of antiviral resistance. These challenges underscore the imperative for developing novel therapeutic strategies. In this framework, naturally occurring compounds have exhibited considerable medical significance attributable to their biological functionalities. Compounds extracted from snake venoms have evidenced antiviral efficacy against a variety of viral pathogens including Orthoflavivirus denguei (DENV), Orthoflavivirus flavi (YFV), Orthoflavivirus zikaense (ZIKV), and HCV. Here, the activity of 10 proteins isolated from snakes' venom of Bothrops genus were evaluated against HCV replicative cycle. JFH-1 HCV system infected Huh-7.5 cell. Cell viability was measured simultaneously through MTT assay. Eight compounds inhibited up to 99 % of HCV infection, with the most potent inhibitory rates observed in BthTX-I and BthTX-II. These exhibited an SI of > 50 and 16,220, respectively, being able to block 84.7 % and 96 % of HCV infectivity. BthTX-II also demonstrated a protective effect in cells treated prior to HCV infection of approximately 86.7 %. Molecular docking calculations suggest interactions between the two proteins with HCV E1E2 glycoprotein complex. BthTX-II exhibited stronger interactions, indicated by 22 hydrophobic interactions. In conclusion, these compounds were shown to inhibit HCV infectivity by either acting on the virus particles or protecting the cells against infection.