RNA Capping, Replication Complex Assembly, and Translational Regulation in Chikungunya Virus: Molecular Mechanisms and Antiviral Opportunities.

Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that has become a significant global public health concern due to its rapid spread and the debilitating acute and chronic joint pain (arthralgia) it causes. Understanding the molecular events that regulate CHIKV RNA synthesis and gene expression is essential for identifying vulnerable stages in the viral life cycle and guiding the development of targeted therapies. This narrative review summarises key aspects of CHIKV molecular biology, focusing on RNA capping, genome replication, and translation. CHIKV RNA capping is primarily facilitated by non-structural protein 1 (nsP1), which has both methyltransferase and guanylyl transferase activities. These activities are necessary for producing the 5' type-0 cap structure (m⁷GpppN), which stabilises viral RNA, enhances translation efficiency, and aids in immune evasion. Viral genome replication takes place within membrane-derived replication spherules that compartmentalise replication complexes composed of nsP1-nsP4 and host cofactors, protecting RNA intermediates from detection by the innate immune system. The RNA-dependent RNA polymerase nsP4 drives the synthesis of negative-strand templates, followed by the amplification of positive-sense genomic RNA and the transcription of 26S sub-genomic RNA for structural protein production. CHIKV also modifies host translation and antiviral signalling to maintain efficient viral protein synthesis. These findings demonstrate that nsP1, nsP2, and nsP4 are promising antiviral targets. They emphasise the importance of understanding CHIKV's molecular mechanisms to develop effective therapeutic strategies against CHIKV and related alphaviruses.