Discovery of Pentacyclic Triterpenoid PROTACs as a Class of Effective Hemagglutinin Protein Degraders

• Published in: Journal of medicinal chemistry 2022-05, Vol.65 (10), p.7154-7169
• Main Authors: Li, Haiwei, Wang, Shouxin, Ma, Wenxiao, Cheng, Boyang, Yi, Yanliang, Ma, Xinyuan, Xiao, Sulong, Zhang, Lihe, Zhou, Demin
• Format: Article
• Language: English
• Subjects: Animals; Chimera - metabolism; Hemagglutinins; Humans; Influenza, Human - drug therapy; Intercellular Signaling Peptides and Proteins; Mice; Proteins - metabolism; Proteolysis; Triterpenes - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02013

Influenza hemagglutinin that drives viral entry into cells via the membrane fusion process is an up-and-coming antiviral drug target. Herein, we described for the first time the design, synthesis, and biological characteristics of a new class of pentacyclic triterpenoid-based proteolysis targeting chimeras (PROTACs) to enhance the degradation of hemagglutinin target. Among these PROTACs, V3 showed the best degradation effect on the hemagglutinin with a median degradation concentration of 1.44 μM in a ubiquitin and proteasome-dependent manner and broad-spectrum anti-influenza A virus activity but not affected the entry of influenza virus. Moreover, intravenous injection of V3 protected mice against influenza A virus-induced toxic effects. Further diazirine-containing photo-crosslinking mass spectrometric analysis of hemagglutinin complexes indicated crosslinking to Asn15, Thr31, and Asn27, a novel target of hemagglutinin. Taken together, our data revealed that oleanolic acid-based PROTACs could degrade hemagglutinin protein, providing a new direction toward the discovery of potential anti-influenza drugs.