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

• Main Authors: Paulo Ricardo Pimenta da Silva Ramos (Author), Melina Mottin (Author), Caroline Sprengel Lima (Author), Letícia R. Assis (Author), Ketllyn Zagato de Oliveira (Author), Nathalya Cristina de Moraes Roso Mesquita (Author), Natasha Marques Cassani (Author), Igor Andrade Santos (Author), Joyce Villa Verde Bastos Borba (Author), Vinícius Alexandre Fiaia Costa (Author), Bruno Junior Neves (Author), Rafael Victorio Carvalho Guido (Author), Glaucius Oliva (Author), Ana Carolina Gomes Jardim (Author), Luis Octávio Regasini (Author), Carolina Horta Andrade (Author)
• Format: Book
• Published: MDPI AG, 2022-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.3390/ph15121493
1424-8247