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
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...
April 12, 2024: Journal of Medicinal Chemistry