Vilazodone derivative D4 potently inhibits SARS-CoV-2 replication, surpassing remdesivir, but via non-METTL3 targets.

The ongoing COVID-19 pandemic, driven by highly transmissible and mutable SARS-CoV-2 variants, underscores a critical need for broad-spectrum antiviral agents to bolster pandemic preparedness. Current therapeutics often face challenges due to viral mutations and limited efficacy against emerging strains. Initial research identified vilazodone as a potential inhibitor of SARS-CoV-2 replication, specifically targeting the host protein METTL3. This mechanism, involving the N6-methyladenosine (m6A) RNA modification pathway, presents a novel therapeutic avenue, prompting further investigation into enhancing its antiviral potency and selectivity.

Building on the initial finding that vilazodone inhibits SARS-CoV-2 via METTL3, the study designed and synthesized a total of 33 vilazodone derivatives. These compounds were developed with the aim of enhancing antiviral potency and improving the selectivity index. The derivatives were subsequently evaluated for their anti-SARS-CoV-2 activity, with their efficacy compared against the established positive control, remdesivir. Additionally, the researchers assessed the binding affinity of these derivatives to the METTL3 protein and their inhibitory activity against METTL3 to probe the mechanistic basis of their antiviral effects.

Among the 33 synthesized vilazodone derivatives, compound D4 emerged as the most potent anti-SARS-CoV-2 agent. Its antiviral activity qualitatively surpassed that of the positive control, remdesivir, demonstrating significant efficacy. > This potent antiviral efficacy, coupled with a favorable therapeutic index, establishes D4 as a strong candidate for further antiviral drug development. However, mechanistic investigations revealed that D4 exhibited only moderate binding to the METTL3 protein and displayed weak inhibitory activity against METTL3. This unexpected finding suggests that D4's potent anti-SARS-CoV-2 activity is likely mediated through alternative, as-yet-unidentified targets, challenging the initial METTL3-targeting hypothesis and opening new avenues for mechanistic research.