Anti-HCMV activity by an irreversible p97 inhibitor LC-1310
- 9 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Medicinal Chemistry Research
- Vol. 30 (2), 440-448
- https://doi.org/10.1007/s00044-020-02679-1
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.Keywords
This publication has 41 references indexed in Scilit:
- Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell deathNature Chemical Biology, 2013
- Valosin-Containing Protein (VCP/p97) Is Required for Poliovirus Replication and Is Involved in Cellular Protein Secretion Pathway in Poliovirus InfectionJournal of Virology, 2012
- Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin systemNature, 2012
- The ERAD Inhibitor Eeyarestatin I Is a Bifunctional Compound with a Membrane-Binding Domain and a p97/VCP Inhibitory GroupPLOS ONE, 2010
- T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infectionsAntiviral Research, 2009
- Fluorescence-based antiviral assay for the evaluation of compounds against vaccinia virus, varicella zoster virus and human cytomegalovirusJournal of Virological Methods, 2008
- Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latencyMedical Microbiology and Immunology, 2007
- Interaction between the Human Cytomegalovirus UL82 Gene Product (pp71) and hDaxx Regulates Immediate-Early Gene Expression and Viral ReplicationJournal of Virology, 2005
- A three-dimensional model to analyze drug-drug interactionsAntiviral Research, 1990
- Effects of a "new" human respiratory virus in volunteers.BMJ, 1967