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

Hepatitis C is a hepatological disorder induced by the Hepacivirus hominis (Hepatitis C virus, HCV), with approximately 170 million individuals estimated to be presently affected globally. 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. The full-length JFH-1 HCV system was used to infect the Huh-7.5 cell. Cell viability was measured simultaneously through MTT assay. Eight compounds inhibited up to 99% of HCV infection, being the most potent inhibitory rates observed in BthTX-I and BthTX-II, with an SI of 13.5 and 1736, respectively, being able to block 84.7% and 96% of HCV infectivity, in the same order. 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 E1-E2 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.