Erica Sanna
| The Coronavirus Helicase as a Drug Target: New Chemical Approaches Against a Conserved Viral Engine |
| Sanna Erica1, Corona Angela1, Lupia Antonio1, Onali Alessia1, Atzenia Giulia1, Demuru Laura1, Meleddu Rita1, Cottiglia Filippo1, Distinto Simona1, Tramontano Enzo1, Maccioni Elias1 1 Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. 8 km 0.700, 09042, Cagliari, Italy |
| Abstract Helicase of human coronaviruses (hCoVs) is responsible for the RNA unwinding in a 5’ to 3’ direction, a process driven by the ATP hydrolysis. Given its crucial role in viral replication and its highly conserved sequence among hCoVs, this enzyme represents a promising and attractive target for the development of new antiviral drugs.[1] In this study, with the goal to identify potential Pan-hCoVs helicase inhibitors, we have rationally designed and synthesized a library of compounds. These compounds were characterized using structural (single-crystal X-ray diffraction) and spectroscopic (NMR, MS) techniques and subsequently, evaluated for their biological activity. Our results revealed that all compounds were able to inhibit both SARS-CoV-2 helicase-associated enzyme activities, namely NTPase and unwinding activity, showing IC50 values in the low micromolar range. Among them, several compounds also demonstrated potent antiviral effects, significantly inhibiting SARS-CoV-2 replication at low EC50 values, without causing notable cytotoxicity (CC50). Furthermore, some of the most promising candidates demonstrated antiviral activity against other human coronaviruses such as MERS-CoV and hCoV-229E, highlighting their potential as pan-hCoV inhibitors. These findings underscore the potential of targeting hCoV helicase as a strategy for developing effective treatments against SARS-CoV-2 and other hCoVs, opening the door to the development of novel therapeutic agents that could address both current and future emerging coronavirus-related diseases. |
| References [1] Spratt, A.N., et al., Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents. Expert Opin Ther Pat, 2021. 31(4): p. 339-350. |