Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

Sven Ullrich; Vishnu M. Sasi; Mithun C. Mahawaththa; Kasuni B. Ekanayake; Richard Morewood; Josemon George; Laura Shuttleworth; Xiaobai Zhang; Cassidy Whitefield; Gottfried Otting; Colin Jackson; Christoph Nitsche

doi:10.1016/j.bmcl.2021.128333

Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

Sven Ullrich, Vishnu M. Sasi, Mithun C. Mahawaththa, Kasuni B. Ekanayake, Richard Morewood, Josemon George, Laura Shuttleworth, Xiaobai Zhang, Cassidy Whitefield, Gottfried Otting, Colin Jackson, Christoph Nitsche

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (M^pro) is an attractive drug target. SARS-CoV-2 M^pro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, M^pro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure–activity relationships, displayed no inhibitory activity at concentrations as high as 100 μM. Only a long linear peptide covering residues P₆ to P₅′ displayed moderate inhibition (K_i = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting M^pro.

Original language	English
Article number	128333
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	50
DOIs	https://doi.org/10.1016/j.bmcl.2021.128333
Publication status	Published - 15 Oct 2021

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title = "Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors",

abstract = "Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure–activity relationships, displayed no inhibitory activity at concentrations as high as 100 μM. Only a long linear peptide covering residues P6 to P5′ displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.",

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author = "Sven Ullrich and Sasi, {Vishnu M.} and Mahawaththa, {Mithun C.} and Ekanayake, {Kasuni B.} and Richard Morewood and Josemon George and Laura Shuttleworth and Xiaobai Zhang and Cassidy Whitefield and Gottfried Otting and Colin Jackson and Christoph Nitsche",

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doi = "10.1016/j.bmcl.2021.128333",

language = "English",

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AU - Sasi, Vishnu M.

AU - Mahawaththa, Mithun C.

AU - Ekanayake, Kasuni B.

AU - Morewood, Richard

AU - George, Josemon

AU - Shuttleworth, Laura

AU - Zhang, Xiaobai

AU - Whitefield, Cassidy

AU - Otting, Gottfried

AU - Jackson, Colin

AU - Nitsche, Christoph

PY - 2021/10/15

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N2 - Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure–activity relationships, displayed no inhibitory activity at concentrations as high as 100 μM. Only a long linear peptide covering residues P6 to P5′ displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.

AB - Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure–activity relationships, displayed no inhibitory activity at concentrations as high as 100 μM. Only a long linear peptide covering residues P6 to P5′ displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.

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KW - Coronaviruses

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KW - SARS-CoV-2

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DO - 10.1016/j.bmcl.2021.128333

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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Challenges of short substrate analogues as SARS-CoV-2 main protease inhibitors

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