Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approva...

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Main Authors: Francesca Picarazzi, Ilaria Vicenti, Francesco Saladini, Maurizio Zazzi, Mattia Mori
Format: Article
Language:English
Published: MDPI AG 2020-12-01
Series:Molecules
Subjects:
RdRp
Mg<sup>2+</sup> ions catalysis
emerging RNA viruses
small molecule inhibitors
structure-based drug design
Online Access:https://www.mdpi.com/1420-3049/25/23/5695
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spelling doaj-e4b054b28cfc4c97a2cc7fdc9d39a92a2020-12-04T00:00:53ZengMDPI AGMolecules1420-30492020-12-01255695569510.3390/molecules25235695Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design ChallengeFrancesca Picarazzi0Ilaria Vicenti1Francesco Saladini2Maurizio Zazzi3Mattia Mori4Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, Via Aldo Moro 2, 53100 Siena, ItalyThe RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses’ story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.https://www.mdpi.com/1420-3049/25/23/5695RdRpMg<sup>2+</sup> ions catalysisemerging RNA virusessmall molecule inhibitorsstructure-based drug design
collection DOAJ
language English
format Article
sources DOAJ
author Francesca Picarazzi
Ilaria Vicenti
Francesco Saladini
Maurizio Zazzi
Mattia Mori
spellingShingle Francesca Picarazzi
Ilaria Vicenti
Francesco Saladini
Maurizio Zazzi
Mattia Mori
Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
Molecules
RdRp
Mg<sup>2+</sup> ions catalysis
emerging RNA viruses
small molecule inhibitors
structure-based drug design
author_facet Francesca Picarazzi
Ilaria Vicenti
Francesco Saladini
Maurizio Zazzi
Mattia Mori
author_sort Francesca Picarazzi
title Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
title_short Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
title_full Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
title_fullStr Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
title_full_unstemmed Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
title_sort targeting the rdrp of emerging rna viruses: the structure-based drug design challenge
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2020-12-01
description The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses’ story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.
topic RdRp
Mg<sup>2+</sup> ions catalysis
emerging RNA viruses
small molecule inhibitors
structure-based drug design
url https://www.mdpi.com/1420-3049/25/23/5695
work_keys_str_mv AT francescapicarazzi targetingtherdrpofemergingrnavirusesthestructurebaseddrugdesignchallenge
AT ilariavicenti targetingtherdrpofemergingrnavirusesthestructurebaseddrugdesignchallenge
AT francescosaladini targetingtherdrpofemergingrnavirusesthestructurebaseddrugdesignchallenge
AT mauriziozazzi targetingtherdrpofemergingrnavirusesthestructurebaseddrugdesignchallenge
AT mattiamori targetingtherdrpofemergingrnavirusesthestructurebaseddrugdesignchallenge
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