Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 440-448 |
Number of pages | 9 |
Journal | Medicinal Chemistry Research |
Volume | 30 |
Issue number | 2 |
Early online date | Jan 9 2021 |
DOIs | |
State | Published - Feb 2021 |
Bibliographical note
Funding Information:The authors wish to acknowledge the Center for Drug Design for support.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
Keywords
- Antiviral
- Human cytomegalovirus
- Valosin-containing protein
- p97
- p97 inhibitors