Recent advances in phytocompounds as potential Chikungunya virus non-structural protein 2 protease antagonists: A systematic review

Background: The mosquito-borne pathogenic alphavirus known as Chikungunya virus (CHIKV) is becoming a greater hazard to public health, which causes thousands of cases annually in both rural and urban areas of many different nations throughout the world. Finding and creating new leads for the CHIKV virus is crucial because there are currently no effective medications or vaccinations against it. The non-structural protein 2 (nsP2) protease has emerged as a promising target for therapeutic intervention due to its crucial role in viral replication. Purpose: This systematic review aims to evaluate recent advances in natural products as inhibitors of the CHIKV nsP2 protease, summarizing current research, identifying promising compounds, and highlighting gaps in the existing knowledge. Study design: A comprehensive literature search was conducted between January 2006, and June 2024 using databases including PubMed, Scopus, Science Direct, and Google Scholar. Search terms included CHIKV, nsP2 protease, antivirals, natural products, phytochemicals, and inhibitors. Studies were selected based on predefined inclusion and exclusion criteria, focusing on original research articles examining natural products as inhibitors of CHIKV nsP2 protease. Methods: Relevant studies were screened, and data were extracted regarding the source of natural compounds, methods of extraction, chemical structures, mechanisms of action, potency, and efficacy in inhibiting nsP2 protease or CHIKV replication. Results: The review included 40 studies, revealing a variety of natural products and their derivatives with inhibitory effects on CHIKV nsP2 protease. Several compounds demonstrated promising inhibitory activity with EC50 values in the micromolar range. Mechanistic studies revealed diverse modes of action, including inhibition of protease activity or interference with viral replication processes. Conclusion: Natural products have gained attention for their diverse chemical structures and bioactivities, offering a rich source of compounds with antiviral potential. We summarize the current knowledge on natural products derived from various sources including flavonoids, alkaloids, terpenoids, polyphenols, and some derivative compounds that have demonstrated inhibitory effects against CHIKV through different mechanisms of action. Overall, this systematic review underscores the importance of exploring natural products as promising candidates for the development of effective therapeutics against Chikungunya fever, particularly through targeting the nsP2 protease.