Exploring the potential of direct-acting antivirals against Chikungunya virus through structure-based drug repositioning and molecular dynamic simulations

The Chikungunya virus (CHIKV) represents a significant global health threat, particularly in tropical regions, and no FDA-approved antiviral treatments are currently available. This study investigates the potential of Direct-Acting Antivirals (DAAs) and protease inhibitors (PIs) that have been developed for the hepatitis C virus (HCV) in treating CHIKV. We analyzed the binding of eight HCV DAAs to the nsP2 protease of CHIKV, which is essential for viral replication. Our findings suggest repurposing hepatitis C virus (HCV) antivirals, specifically Simeprevir (SIM) and voxilaprevir (VOX), could be effective against CHIKV. Through computational analyses, we observed their strong binding affinity to CHIKV's nsP2 protease, indicating the promising potential of repositioning these drugs for CHIKV treatment. To validate the results of our computational study, we evaluated the antiviral efficacy of SIM and VOX in vitro, both as monotherapies and in combination with ribavirin (RIBA). Our findings revealed that DAAs exert a multifaced effect by targeting different stages of the CHIKV life cycle. Furthermore, the synergistic effects suggest that combining SIM and VOX with RIBA may provide a more effective therapeutic strategy than using either drug alone. Further research is necessary to optimize treatment protocols and improve outcomes for patients affected by CHIKV.