Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Yugendar R. Alugubelli; Jing Xiao; Kaustav Khatua; Sathish Kumar; Long Sun; Yuying Ma; Xinyu R. Ma; Veerabhadra R. Vulupala; Sandeep Atla; Lauren R. Blankenship; Demonta Coleman; Xuping Xie; Benjamin W. Neuman; Wenshe Ray Liu; Shiqing Xu

doi:10.1021/acs.jmedchem.3c02416

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Yugendar R. Alugubelli
, Jing Xiao
, Kaustav Khatua
, Sathish Kumar
, Long Sun
, Yuying Ma
, Xinyu R. Ma
, Veerabhadra R. Vulupala
, Sandeep Atla
, Lauren R. Blankenship
, Demonta Coleman
, Xuping Xie
, Benjamin W. Neuman
, Wenshe Ray Liu
, Shiqing Xu

Microbiology And Immunology

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

49 Scopus citations

Abstract

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M^Pro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M^Pro. Among them, MPD2 was demonstrated to effectively reduce M^Pro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M^Pro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of M^Pro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

Original language	English (US)
Pages (from-to)	6495-6507
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	67
Issue number	8
DOIs	https://doi.org/10.1021/acs.jmedchem.3c02416
State	Published - Apr 25 2024

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.3c02416

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title = "Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease",

abstract = "We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Among them, MPD2 was demonstrated to effectively reduce MPro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of MPro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.",

author = "Alugubelli, \{Yugendar R.\} and Jing Xiao and Kaustav Khatua and Sathish Kumar and Long Sun and Yuying Ma and Ma, \{Xinyu R.\} and Vulupala, \{Veerabhadra R.\} and Sandeep Atla and Blankenship, \{Lauren R.\} and Demonta Coleman and Xuping Xie and Neuman, \{Benjamin W.\} and Liu, \{Wenshe Ray\} and Shiqing Xu",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Published by American Chemical Society",

year = "2024",

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doi = "10.1021/acs.jmedchem.3c02416",

language = "English (US)",

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T1 - Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

AU - Alugubelli, Yugendar R.

AU - Xiao, Jing

AU - Khatua, Kaustav

AU - Kumar, Sathish

AU - Sun, Long

AU - Ma, Yuying

AU - Ma, Xinyu R.

AU - Vulupala, Veerabhadra R.

AU - Atla, Sandeep

AU - Blankenship, Lauren R.

AU - Coleman, Demonta

AU - Xie, Xuping

AU - Neuman, Benjamin W.

AU - Liu, Wenshe Ray

AU - Xu, Shiqing

PY - 2024/4/25

Y1 - 2024/4/25

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AB - We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Among them, MPD2 was demonstrated to effectively reduce MPro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of MPro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

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Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Abstract

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