Multiple effects of toxins isolated from Crotalus durissus terrificus on the hepatitis C virus life cycle

Abstract

Hepatitis C virus (HCV) is one of the main causes of liver disease and transplantation worldwide. Current therapy is expensive, presents additional side effects and viral resistance has been described. Therefore, studies for developing more efficient antivirals against HCV are needed. Compounds isolated from animal venoms have shown antiviral activity against some viruses such as Dengue virus, Yellow fever virus and Measles virus. In this study, we evaluated the effect of the complex crotoxin (CX) and its subunits crotapotin (CP) and phospholipase A2 (PLA2-CB) isolated from the venom of Crotalus durissus terrificus on HCV life cycle. Huh 7.5 cells were infected with HCVcc JFH-1 strain in the presence or absence of these toxins and virus was titrated by focus formation units assay or by qPCR. Toxins were added to the cells at different time points depending on the stage of virus life cycle to be evaluated. The results showed that treatment with PLA2-CB inhibited HCV entry and replication but no effect on HCV release was observed. CX reduced virus entry and release but not replication. By treating cells with CP, an antiviral effect was observed on HCV release, the only stage inhibited by this compound. Our data demonstrated the multiple antiviral effects of toxins from animal venoms on HCV life cycle.

Insights into the antiviral activity of phospholipases A2 (PLA2s) from snake venoms

“…The development of efficient antiviral therapies has become a global health emergency. In this sense, several researches have demonstrated the antiviral activity of sPLA 2 s from snake venom against human viruses, including DENV, YFV, HCV and others [ [88] , [89] , [90] , [91] , [92] ]. Hence, the present review aimed to summarize the sPLA 2 s from snake venom that were previously described to possess antiviral activity, highlighting the mechanisms of action of sPLA 2 s against different stages of virus replication cycle ( Table 1 ).…”

“…In order to gain insights into the antiviral mechanism of sPLA 2 s obtained from C. t. terrificus , Shimizu and colleagues [ 90 ] showed that PLA 2 -CB inhibited HCVcc JFH-1 virus strain entry and replication in Huh 7.5 cells, and crotoxin blocked virus entry and release, suggesting that these proteins possess multiple antiviral effects against HCV. Moreover, the authors also reported that PLA 2 -CB significantly decrease the levels of lipid droplets, which are essential for the HCV replication complex, and reduced the levels of HCV NS5A protein due to the replication inhibition, evidencing that besides the action on virus entry, PLA 2 -CB is able to disrupt HCV replication probably by an interference in lipid metabolism of host cell [ 90 , 100 , 101 ].…”

“…Regarding the virucidal activity, studies have shown that both catalytically-active sPLA 2 s (crotoxin, PLA 2 -IC, PLA 2 -CB, Mt-I and CM-II-sPLA 2 ) and catalytically-inactive sPLA 2 s (Mt-II and BthTX-I) indicated virucidal activity preferentially against enveloped viruses, such as DENV (serotypes 1, 2 and 3), YFV, ROCV, OROV, MAYV, HCV, JEV, MERS-CoV, SINV, FLUAV, SeV, VSNJV, HIV-1 and HSV-1 [ [88] , [89] , [90] , 92 , 114 ].…”

“…Independent studies have revealed that sPLA 2 s such as crotoxin, PLA 2 -IC, PLA 2 -CB, Bl-PLA 2 and BthTX-I are also able to dramatically impact the entry, replication and release of viruses by targeting host cell components [ [88] , [89] , [90] , [91] ]. To gain insights into these viral cycle stages, it was demonstrated that Nmm CMIII , taipoxin and nigexine prevented the intracellular release of HIV-1 Gap p24 proteins from the viral capsid (inhibition virus entry) by a direct binding to membrane receptors of host cells [ 107 ].…”

“…To gain insights into these viral cycle stages, it was demonstrated that Nmm CMIII , taipoxin and nigexine prevented the intracellular release of HIV-1 Gap p24 proteins from the viral capsid (inhibition virus entry) by a direct binding to membrane receptors of host cells [ 107 ]. In addition, PLA 2 -CB was able to disrupt HCV replication probably by an interference in lipid metabolism of host cell [ 90 ].…”