COVID-19, caused by SARS-CoV-2, led to global health and economic crises. While vaccines have been developed, challenges remain, including multi-dose requirements, varying efficacy, and emerging variants. This highlights the urgent need for new antivirals, such as small-molecule drugs targeting essential viral proteins and nucleic acids.

RNA-targeting small-molecule antivirals are emerging as a promising approach, offering broader antiviral potential by targeting conserved RNA structures like RNA G-quadruplexes (RGQs) in viruses. These structures, conserved across beta coronaviruses, provide resistance to mutations, enhancing efficacy against diverse variants, but remain an underexplored area in antiviral development.

The nucleocapsid gene of SARS-CoV-2, responsible for viral packaging, contains GG repeats that could fold into unstable two-tetrad G-quadruplex (GQ) motifs. In this study, we have developed the small drugs, i.e., TPE derivatives, that interact with the GQ structure of the nucleocapsid gene. These small molecules further facilitate the folding and stabilization of unstable two-tetrad GQs to stable GQs, subsequently resulting in the inhibition of post-entry stages of the viral replication cycle, such as viral replication, viral packaging, and formation of new virions. 

These findings demonstrate that TPE derivatives have antiviral therapeutic potential by inhibiting crucial gene expression in SARS-CoV-2.

Research Article: Gupta, P., Khadake, R.M., Singh, O.N., Mirgane, H.A., Gupta, D., Bhosale, S.V., Vrati, S., Surjit, M. and Rode, A.B. Targeting Two-Tetrad RNA G-Quadruplex in the SARS-CoV-2 RNA Genome Using Tetraphenylethene Derivatives for Antiviral Therapy. ACS Infectious Diseases. 2025 Feb 27;11(3):784-795.