Anti-HCMV activity by an irreversible p97 inhibitor LC-1310
- Med Chem Res. 2021;30(2):440-448. doi: 10.1007/s00044-020-02679-1.
- 1. Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455 USA.
- 2. Present Address: Translational Medicine R&D Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055 China.
The AAA+ (ATPase associated with various cellular activities) protein p97, also called valosin-containing protein, is a hexameric ring ATPase and uses ATP hydrolysis to unfold or extract proteins from biological complexes. Many cellular processes are affected by p97 including ER-associated degradation, DNA damage response, cell signaling (NF-κB), cell cycle progression, Autophagy, and Others. Not surprisingly, with its role in many fundamental cellular processes, p97 function is important for the replication of many viruses. We tested irreversible p97-targeting compounds for their ability to inhibit the replication of multiple viruses compared to the known p97 inhibitors NMS-873 and CB-5083. Our results indicate that overall cellular toxicity for p97 compounds provides a challenge for antivirals targeting p97. However, we identified one compound with sub-micromolar activity against human cytomegalovirus and improved cell viability to provide evidence for the potential of irreversible p97 inhibitors as antivirals.