Repurposing tirbanibulin as an orally active E2-targeting entry inhibitor against Chikungunya virus

Chikungunya virus (CHIKV) causes severe acute and chronic disease, yet no approved specific antiviral treatment exists. To rapidly identify potential treatments, we aimed to screen an FDA-approved drug library for inhibitors of CHIKV infection. Tirbanibulin, a dual-microtubule polymerization and Src kinase inhibitor, was assessed for its potential anti-CHIKV activity.

We performed a high-throughput screen of an FDA-approved drug library. Mechanism-of-action studies included entry-step analysis, surface plasmon resonance (SPR) binding assays and molecular docking. In vivo efficacy was evaluated in lethal murine neuroinfection and CHIKV-induced arthritis models following oral administration of the candidate compound.

Tirbanibulin exhibited nanomolar to low-micromolar antiviral activity (EC₅₀ range: 0.035-75.64 μM) across multiple cell lines, with high selective indices in key target HT22 and Huh7 cells. It acted at a post-attachment entry step, inhibiting clathrin-mediated endocytosis and potentially viral fusion. Surface plasmon resonance confirmed direct, high-affinity binding to the CHIKV E1 and E2 glycoprotein complex (K_D = 73 nM). In the lethal neuroinfection model, oral tirbanibulin significantly improved survival and reduced brain viral loads; in the arthritis model, it markedly attenuated footpad swelling and inflammatory pathology.

Tirbanibulin is a novel, orally bioavailable entry-stage inhibitor that directly targets the E2 glycoprotein. Multiple preclinical and clinical studies have confirmed its favourable oral bioavailability and safety. Given its established clinical safety profile, it represents a promising repurposing candidate for clinical evaluation against Chikungunya fever.