NIH Research Festival
Although several drugs and vaccines targeting viral proteins have been deployed against SARS-CoV-2 continued emergence of new variants will likely lead to rapid development of resistance to these therapeutics. An alternative approach is to target host mechanisms essential for the viral life cycle. Here we describe the development of a new anti-viral lead compound, UNC7844, which targets multiple host pathways. UNC7844 inhibits replication of several coronavirus types by more than four orders of magnitude in different cell lines in a low micromolar range. This compound also significantly inhibits liver infection in mice infected with MHV accompanied by reduced expression of inflammatory and fibrosis genes. Preliminary data points to potential in-vivo activity against SARS-CoV-2 in ACE2-expressing mice. Kinetics analysis and time of addition assays revealed that UNC7844 inhibits early phases of viral life cycle between viral entry and replication. UNC7844 inhibits several kinases in the inositol (pyro)phosphate pathway, including IP6K and IPMK, in a low nanomolar range. Overexpression of IPMK in IPMK KO cells elevated viral RNA levels of 229E coronavirus demonstrating a positive role of this kinase in viral replication. Specific IPMK and IP6K inhibitors brought the levels of MHV RNA in IPMK-overexpressing cells to those found in IPMK KO cells. However, UNC7844 exhibits superior inhibition of viral replication, suggesting its mechanisms of antiviral action include additional targets. In summary, our work identifies a novel role of inositol phosphate kinases in coronavirus replication and discloses a new lead compound for targeting host processes involved in viral replication.
Scientific Focus Area: Virology
This page was last updated on Monday, September 25, 2023