Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches.

Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.

Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors.

Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational and experimental approaches have been employed to find a solution to this problem. While the global vaccination campaigns are the primary driver of controlling the current pandemic, orally bioavailable small-molecule drugs and biologics are critical to overcome this global issue. Improved therapeutics and prophylactics are required to treat people with circulating and emerging new variants, addressing severe infection, and people with underlying or immunocompromised conditions. The SARS-CoV-2 envelope spike is a challenging target for viral entry inhibitors. Pindolol presented a good docking score in a previous virtual screening using computational docking calculations after screening a Food and Drug Administration (FDA)-approved drug library of 2400 molecules as potential candidates to block the SARS-CoV-2 spike protein interaction with the angiotensin-converting enzyme 2 (ACE-2). Here, we expanded the computational evaluation to identify five beta-blockers against SARS-CoV-2 using several techniques, such as microscale thermophoresis, NanoDSF, and in vitro assays in different cell lines. These data identified carvedilol with a K d of 364 ± 22 nM for the SARS-CoV-2 spike and in vitro activity (EC50 of 7.57 µM, CC50 of 18.07 µM) against SARS-CoV-2 in Calu-3 cells. We have shown how we can apply multiple computational and experimental approaches to find molecules that can be further optimized to improve anti-SARS-CoV-2 activity.