tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Jing Xiao[SUP] 1 [/SUP], Kaustav Khatua[SUP] 1 [/SUP], Sathish Kumar[SUP] 2 [/SUP], Long Sun[SUP] 3 [/SUP], Yuying Ma[SUP] 1 [/SUP], Xinyu R Ma[SUP] 1 [/SUP], Veerabhadra R Vulupala[SUP] 1 [/SUP], Sandeep Atla[SUP] 1 [/SUP], Lauren R Blankenship[SUP] 1 [/SUP], Demonta Coleman[SUP] 1 [/SUP], Xuping Xie[SUP] 3 [/SUP], Benjamin W Neuman[SUP] 2 4 [/SUP], Wenshe Ray Liu[SUP] 1 5 6 7 [/SUP], Shiqing Xu[SUP] 1 8 [/SUP]
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 (M[SUP]Pro[/SUP]), 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[SUP]Pro[/SUP]. Among them, MPD2 was demonstrated to effectively reduce M[SUP]Pro[/SUP] protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M[SUP]Pro[/SUP] 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[SUP]Pro[/SUP] 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[SUP] 1 [/SUP], Jing Xiao[SUP] 1 [/SUP], Kaustav Khatua[SUP] 1 [/SUP], Sathish Kumar[SUP] 2 [/SUP], Long Sun[SUP] 3 [/SUP], Yuying Ma[SUP] 1 [/SUP], Xinyu R Ma[SUP] 1 [/SUP], Veerabhadra R Vulupala[SUP] 1 [/SUP], Sandeep Atla[SUP] 1 [/SUP], Lauren R Blankenship[SUP] 1 [/SUP], Demonta Coleman[SUP] 1 [/SUP], Xuping Xie[SUP] 3 [/SUP], Benjamin W Neuman[SUP] 2 4 [/SUP], Wenshe Ray Liu[SUP] 1 5 6 7 [/SUP], Shiqing Xu[SUP] 1 8 [/SUP]
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 (M[SUP]Pro[/SUP]), 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[SUP]Pro[/SUP]. Among them, MPD2 was demonstrated to effectively reduce M[SUP]Pro[/SUP] protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M[SUP]Pro[/SUP] 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[SUP]Pro[/SUP] as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.