TY - JOUR
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
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society
PY - 2024/4/25
Y1 - 2024/4/25
N2 - 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.
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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U2 - 10.1021/acs.jmedchem.3c02416
DO - 10.1021/acs.jmedchem.3c02416
M3 - Article
C2 - 38608245
AN - SCOPUS:85190858511
SN - 0022-2623
VL - 67
SP - 6495
EP - 6507
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 8
ER -