The structural model of Zika virus RNA-dependent RNA polymerase in complex with RNA for rational design of novel nucleotide inhibitors

• Published in: Scientific reports Vol. 8; no. 1; pp. 11132 - 13
• Main Authors: Šebera, Jakub, Dubankova, Anna, Sychrovský, Vladimír, Ruzek, Daniel, Boura, Evzen, Nencka, Radim
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.07.2018; Nature Publishing Group
• Subjects: 119/118; 631/114/2397; 631/326/596; Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - pharmacology; Antiviral agents; DNA-directed RNA polymerase; Fetuses; Global health; Health risks; Humanities and Social Sciences; Humans; Magnesium; Magnesium - chemistry; Models, Molecular; Molecular Docking Simulation; multidisciplinary; Nucleoside analogs; Nucleosides - chemistry; Nucleotide analogs; Nucleotides - chemistry; Polyphosphates - chemistry; Protein Conformation - drug effects; RNA - chemistry; RNA - genetics; RNA polymerase; RNA Replicase - chemistry; RNA Replicase - genetics; RNA viruses; RNA-directed RNA polymerase; Science; Science (multidisciplinary); Vaccination; Vector-borne diseases; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Virus Replication - genetics; Zika virus; Zika Virus - chemistry; Zika Virus - genetics; Zika Virus - pathogenicity; Zika Virus Infection - genetics; Zika Virus Infection - virology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-29459-7

Zika virus is a global health threat due to significantly elevated risk of fetus malformations in infected pregnant women. Currently, neither an effective therapy nor a prophylactic vaccination is available for clinical use, desperately necessitating novel therapeutics and approaches to obtain them. Here, we present a structural model of the Zika virus RNA-dependent RNA polymerase (ZIKV RdRp) in complex with template and nascent RNAs, Mg 2+ ions and accessing nucleoside triphosphate. The model allowed for docking studies aimed at effective pre-screening of potential inhibitors of ZIKV RdRp. Applicability of the structural model for docking studies was illustrated with the NITD008 artificial nucleotide that is known to effectively inhibit the function of the ZIKV RdRp. The ZIKV RdRp – RNA structural model is provided for all possible variations of the nascent RNA bases pairs to enhance its general utility in docking and modelling experiments. The developed model makes the rational design of novel nucleosides and nucleotide analogues feasible and thus provides a solid platform for the development of advanced antiviral therapy.