Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2

The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 proteas...

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Main Authors: Davide Gentile, Lucia Chiummiento, Alessandro Santarsiere, Maria Funicello, Paolo Lupattelli, Antonio Rescifina, Assunta Venuti, Anna Piperno, Maria Teresa Sciortino, Rosamaria Pennisi
Format: Article
Language:English
Published: MDPI AG 2024-02-01
Series:Viruses
Subjects:
Online Access:https://www.mdpi.com/1999-4915/16/3/338
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author Davide Gentile
Lucia Chiummiento
Alessandro Santarsiere
Maria Funicello
Paolo Lupattelli
Antonio Rescifina
Assunta Venuti
Anna Piperno
Maria Teresa Sciortino
Rosamaria Pennisi
author_facet Davide Gentile
Lucia Chiummiento
Alessandro Santarsiere
Maria Funicello
Paolo Lupattelli
Antonio Rescifina
Assunta Venuti
Anna Piperno
Maria Teresa Sciortino
Rosamaria Pennisi
author_sort Davide Gentile
collection DOAJ
description The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CL<sup>pro</sup> of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell–virus interaction. The results reported a mild activity against the viral proteases 3CL<sup>pro</sup> and PL<sup>pro</sup>, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.
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spelling doaj.art-33477011c2c14ff4a9b9644772bd60c22024-03-27T14:07:36ZengMDPI AGViruses1999-49152024-02-0116333810.3390/v16030338Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2Davide Gentile0Lucia Chiummiento1Alessandro Santarsiere2Maria Funicello3Paolo Lupattelli4Antonio Rescifina5Assunta Venuti6Anna Piperno7Maria Teresa Sciortino8Rosamaria Pennisi9Department of Chemistry, Materials and Chemical Engineering “G. Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, ItalyDepartment of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, ItalyDepartment of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, ItalyDepartment of Scienze, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, ItalyDepartment of Chimica, Sapienza University of Roma, p. le Aldo Moro 5, 00185 Roma, ItalyDepartment of Drug and Health Sciences, University of Catania, V. le A. Doria, 95125 Catania, ItalyInternational Agency for Research on Cancer (IARC), World Health Organization, 69366 LYON CEDEX 07, FranceDepartment of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, ItalyThe continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CL<sup>pro</sup> of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell–virus interaction. The results reported a mild activity against the viral proteases 3CL<sup>pro</sup> and PL<sup>pro</sup>, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.https://www.mdpi.com/1999-4915/16/3/338SARS-CoV-2cysteine proteasepseudovirus technology
spellingShingle Davide Gentile
Lucia Chiummiento
Alessandro Santarsiere
Maria Funicello
Paolo Lupattelli
Antonio Rescifina
Assunta Venuti
Anna Piperno
Maria Teresa Sciortino
Rosamaria Pennisi
Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
Viruses
SARS-CoV-2
cysteine protease
pseudovirus technology
title Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
title_full Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
title_fullStr Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
title_full_unstemmed Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
title_short Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2
title_sort targeting viral and cellular cysteine proteases for treatment of new variants of sars cov 2
topic SARS-CoV-2
cysteine protease
pseudovirus technology
url https://www.mdpi.com/1999-4915/16/3/338
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