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

Influenza hemagglutinin that drives viral entry intocells via the membrane fusion process is an up-and-coming antiviraldrug target. Herein, we described for thefirst time the design,synthesis, and biological characteristics of a new class of pentacyclictriterpenoid-based proteolysis targeting chimeras (PROTACs) toenhance the degradation of hemagglutinin target. Among thesePROTACs,V3showed the best degradation effect on thehemagglutinin with a median degradation concentration of 1.44 mu M in a ubiquitin and proteasome-dependent manner and broad-spectrum anti-influenza A virus activity but not affected the entry ofinfluenza virus. Moreover, intravenous injection ofV3protectedmice against influenza A virus-induced toxic effects. Further diazirine-containing photo-crosslinking mass spectrometric analysis ofhemagglutinin complexes indicated crosslinking to Asn15, Thr31, and Asn27, a novel target of hemagglutinin. Taken together, ourdata revealed that oleanolic acid-based PROTACs could degrade hemagglutinin protein, providing a new direction toward thediscovery of potential anti-influenza drugs