Tweet
J Med Chem
. 2024 Apr 12.
doi: 10.1021/acs.jmedchem.3c02416. Online ahead of print. Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease
Yugendar R Alugubelli 1 , Jing Xiao 1 , Kaustav Khatua 1 , Sathish Kumar 2 , Long Sun 3 , Yuying Ma 1 , Xinyu R Ma 1 , Veerabhadra R Vulupala 1 , Sandeep Atla 1 , Lauren R Blankenship 1 , Demonta Coleman 1 , Xuping Xie 3 , Benjamin W Neuman 2 4 , Wenshe Ray Liu 1 5 6 7 , Shiqing Xu 1 8
Affiliations
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.
. 2024 Apr 12.
doi: 10.1021/acs.jmedchem.3c02416. Online ahead of print. Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease
Yugendar R Alugubelli 1 , Jing Xiao 1 , Kaustav Khatua 1 , Sathish Kumar 2 , Long Sun 3 , Yuying Ma 1 , Xinyu R Ma 1 , Veerabhadra R Vulupala 1 , Sandeep Atla 1 , Lauren R Blankenship 1 , Demonta Coleman 1 , Xuping Xie 3 , Benjamin W Neuman 2 4 , Wenshe Ray Liu 1 5 6 7 , Shiqing Xu 1 8
Affiliations
- PMID: 38608245
- DOI: 10.1021/acs.jmedchem.3c02416
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.