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, R. Xinyu, Veerabhadra R. Vulupala, Sandeep Atla, Lauren R. Blankenship, Demonta Coleman, Xuping Xie, Benjamin W. Neuman, Wenshe Ray Liu, Shiqing Xu
Abstract
High Resolution Image Download MS PowerPoint Slide 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.