Zeolitic imidazolate frameworks for delivery of repurposed drugs with anti-chikungunya activity

Chikungunya virus (CHIKV) is a major global concern due to its emergence and re-emergence and the lack of effective antiviral treatments. Conventional antiviral drugs struggle with poor bioavailability, rapid degradation, and cytotoxicity, limiting their effectiveness. Nanoparticle-based drug delivery systems, particularly Zeolitic Imidazolate Frameworks (ZIF-C), have shown potential in improving the therapeutic outcomes of antiviral drugs. We encapsulated four repurposed drugs - Enalaprilat, Lomibuvir, Metyrapone, and Resveratrol within ZIF-C. Cytotoxicity assay of the formulations (ZIF-C(E), ZIF-C(L), ZIF-C(M), and ZIF-C(R)) show that free Enalaprilat, Lomibuvir, Metyrapone, and Resveratrol are toxic above 1.56 µM, 6.25 µM, 200 µM, and 12.5 µM, respectively, while their ZIF-C counterparts maintain >90 % cell viability even at 50-100 µM. Antiviral studies further show that ZIF-C(E), ZIF-C(L), ZIF-C(M), and ZIF-C(R) reduce CHIKV viral titers by 3.8, 3.8, 2.9, and 3.9 logs, respectively, with reference to virus control (VC), while the free drugs Enalaprilat, Lomibuvir, Metyrapone, and Resveratrol show 0.7, 0.7, 0.01, and 0.8 log reduction, respectively. Empty ZIF-C nanoparticles exhibit negligible antiviral effects. The results suggest that encapsulation within ZIF-C nanoparticles can help improve the stability, delivery, and effectiveness of antiviral drugs. This could be a promising strategy for treating CHIKV and other viral infections.