G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters

The COVID-19 pandemic caused by SARS-CoV-2 has caused millions of infections and deaths worldwide. Limited treatment options and the threat from emerging variants underline the need for novel and widely accessible therapeutics. G-quadruplexes (G4s) are nucleic acid secondary structures known to affe...

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Main Authors: Shuvra Shekhar Roy, Shalu Sharma, Zaigham Abbas Rizvi, Dipanjali Sinha, Divya Gupta, Mercy Rophina, Paras Sehgal, Srikanth Sadhu, Manas Ranjan Tripathy, Sweety Samal, Souvik Maiti, Vinod Scaria, Sridhar Sivasubbu, Amit Awasthi, Krishnan H. Harshan, Sanjeev Jain, Shantanu Chowdhury
Format: Article
Language:English
Published: Frontiers Media S.A. 2023-03-01
Series:Frontiers in Molecular Biosciences
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fmolb.2023.1133123/full
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author Shuvra Shekhar Roy
Shuvra Shekhar Roy
Shalu Sharma
Shalu Sharma
Zaigham Abbas Rizvi
Dipanjali Sinha
Dipanjali Sinha
Divya Gupta
Mercy Rophina
Mercy Rophina
Paras Sehgal
Paras Sehgal
Srikanth Sadhu
Manas Ranjan Tripathy
Sweety Samal
Souvik Maiti
Souvik Maiti
Souvik Maiti
Vinod Scaria
Vinod Scaria
Sridhar Sivasubbu
Sridhar Sivasubbu
Amit Awasthi
Krishnan H. Harshan
Krishnan H. Harshan
Sanjeev Jain
Shantanu Chowdhury
Shantanu Chowdhury
author_facet Shuvra Shekhar Roy
Shuvra Shekhar Roy
Shalu Sharma
Shalu Sharma
Zaigham Abbas Rizvi
Dipanjali Sinha
Dipanjali Sinha
Divya Gupta
Mercy Rophina
Mercy Rophina
Paras Sehgal
Paras Sehgal
Srikanth Sadhu
Manas Ranjan Tripathy
Sweety Samal
Souvik Maiti
Souvik Maiti
Souvik Maiti
Vinod Scaria
Vinod Scaria
Sridhar Sivasubbu
Sridhar Sivasubbu
Amit Awasthi
Krishnan H. Harshan
Krishnan H. Harshan
Sanjeev Jain
Shantanu Chowdhury
Shantanu Chowdhury
author_sort Shuvra Shekhar Roy
collection DOAJ
description The COVID-19 pandemic caused by SARS-CoV-2 has caused millions of infections and deaths worldwide. Limited treatment options and the threat from emerging variants underline the need for novel and widely accessible therapeutics. G-quadruplexes (G4s) are nucleic acid secondary structures known to affect many cellular processes including viral replication and transcription. We identified heretofore not reported G4s with remarkably low mutation frequency across >5 million SARS-CoV-2 genomes. The G4 structure was targeted using FDA-approved drugs that can bind G4s - Chlorpromazine (CPZ) and Prochlorperazine (PCZ). We found significant inhibition in lung pathology and lung viral load of SARS-CoV-2 challenged hamsters when treated with CPZ or PCZ that was comparable to the widely used antiviral drug Remdesivir. In support, in vitro G4 binding, inhibition of reverse transcription from RNA isolated from COVID-infected humans, and attenuated viral replication and infectivity in Vero cell cultures were clear in case of both CPZ and PCZ. Apart from the wide accessibility of CPZ/PCZ, targeting relatively invariant nucleic acid structures poses an attractive strategy against viruses like SARS-CoV-2, which spread fast and accumulate mutations quickly.
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spelling doaj.art-be185dc57a37426ca40b3079c5373adf2023-03-16T07:22:14ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-03-011010.3389/fmolb.2023.11331231133123G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamstersShuvra Shekhar Roy0Shuvra Shekhar Roy1Shalu Sharma2Shalu Sharma3Zaigham Abbas Rizvi4Dipanjali Sinha5Dipanjali Sinha6Divya Gupta7Mercy Rophina8Mercy Rophina9Paras Sehgal10Paras Sehgal11Srikanth Sadhu12Manas Ranjan Tripathy13Sweety Samal14Souvik Maiti15Souvik Maiti16Souvik Maiti17Vinod Scaria18Vinod Scaria19Sridhar Sivasubbu20Sridhar Sivasubbu21Amit Awasthi22Krishnan H. Harshan23Krishnan H. Harshan24Sanjeev Jain25Shantanu Chowdhury26Shantanu Chowdhury27CSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaImmuno-biology Laboratory, Infection and Immunology Centre, Translational Health Science and Technology Institute, Faridabad, 121001, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaImmuno-biology Laboratory, Infection and Immunology Centre, Translational Health Science and Technology Institute, Faridabad, 121001, IndiaImmuno-biology Laboratory, Infection and Immunology Centre, Translational Health Science and Technology Institute, Faridabad, 121001, IndiaTranslational Health Science and Technology Institute, Faridabad, 411008, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-National Chemical Laboratory, Pune, 121001, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaImmuno-biology Laboratory, Infection and Immunology Centre, Translational Health Science and Technology Institute, Faridabad, 121001, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaCSIR-Centre for Cellular and Molecular Biology, Hyderabad, 500007, IndiaMolecular Genetics Laboratory, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, IndiaCSIR-Institute of Genomics & Integrative Biology, New Delhi, 110025, IndiaAcademy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, IndiaThe COVID-19 pandemic caused by SARS-CoV-2 has caused millions of infections and deaths worldwide. Limited treatment options and the threat from emerging variants underline the need for novel and widely accessible therapeutics. G-quadruplexes (G4s) are nucleic acid secondary structures known to affect many cellular processes including viral replication and transcription. We identified heretofore not reported G4s with remarkably low mutation frequency across >5 million SARS-CoV-2 genomes. The G4 structure was targeted using FDA-approved drugs that can bind G4s - Chlorpromazine (CPZ) and Prochlorperazine (PCZ). We found significant inhibition in lung pathology and lung viral load of SARS-CoV-2 challenged hamsters when treated with CPZ or PCZ that was comparable to the widely used antiviral drug Remdesivir. In support, in vitro G4 binding, inhibition of reverse transcription from RNA isolated from COVID-infected humans, and attenuated viral replication and infectivity in Vero cell cultures were clear in case of both CPZ and PCZ. Apart from the wide accessibility of CPZ/PCZ, targeting relatively invariant nucleic acid structures poses an attractive strategy against viruses like SARS-CoV-2, which spread fast and accumulate mutations quickly.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1133123/fullRNA G-quadruplexFDA-approved drugsG-quadruplex binding drugshamster model of COVID-19Conserved motif
spellingShingle Shuvra Shekhar Roy
Shuvra Shekhar Roy
Shalu Sharma
Shalu Sharma
Zaigham Abbas Rizvi
Dipanjali Sinha
Dipanjali Sinha
Divya Gupta
Mercy Rophina
Mercy Rophina
Paras Sehgal
Paras Sehgal
Srikanth Sadhu
Manas Ranjan Tripathy
Sweety Samal
Souvik Maiti
Souvik Maiti
Souvik Maiti
Vinod Scaria
Vinod Scaria
Sridhar Sivasubbu
Sridhar Sivasubbu
Amit Awasthi
Krishnan H. Harshan
Krishnan H. Harshan
Sanjeev Jain
Shantanu Chowdhury
Shantanu Chowdhury
G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
Frontiers in Molecular Biosciences
RNA G-quadruplex
FDA-approved drugs
G-quadruplex binding drugs
hamster model of COVID-19
Conserved motif
title G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
title_full G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
title_fullStr G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
title_full_unstemmed G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
title_short G4-binding drugs, chlorpromazine and prochlorperazine, repurposed against COVID-19 infection in hamsters
title_sort g4 binding drugs chlorpromazine and prochlorperazine repurposed against covid 19 infection in hamsters
topic RNA G-quadruplex
FDA-approved drugs
G-quadruplex binding drugs
hamster model of COVID-19
Conserved motif
url https://www.frontiersin.org/articles/10.3389/fmolb.2023.1133123/full
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