Recent progress in anti-Chikungunya virus drug discovery: Focus on the viral life cycle and direct-acting antivirals.

Chikungunya virus (CHIKV) belongs to the genus Alphavirus of the family Togaviridae. CHIKV infection generally causes severe clinical symptoms, including debilitating arthralgia, fever, hemorrhage and cutaneous rashes. In recent years, the transmission range of CHIKV has continued to expand, resulting in recurrent local outbreaks in densely populated and economically developed regions and posing a severe threat to public health. Accordingly, safe and effective anti-CHIKV therapeutics are urgently needed for the clinical treatment of infected patients. Nevertheless, no specific anti-CHIKV drugs have been approved for clinical use or advanced into clinical trials, and relevant research and development remain confined to the preclinical stage. This review systematically illustrates the key steps of the CHIKV life cycle, core viral components and vital functional domains, and summarizes the current research progress of anti-CHIKV agents. It comprehensively outlines the discovery strategies, structural optimization directions and activity evaluation approaches of anti-CHIKV small-molecule compounds, and further investigates their action targets. Notably, nsP2 and nsP4 represent promising targets for broad-spectrum anti-CHIKV even anti-alphavirus drug development due to their structural conservation across alphavirus species and druggable features. This work provides a solid theoretical basis and valuable reference for the future research and development of novel anti-CHIKV drugs.