Viral infection results in both acute and chronic pathologies encompassing a wide range of symptoms. As an example, influenza virus affects three to five million people and results in 250,000 to 500,000 deaths every year worldwide, rising dramatically during pandemics. Effective preventative protocols do not exist for most viral pathogens and there are few successful post-infection treatments. Generation of new membranes or lipid structures in infected cells is required for viral replication of many pathogenic viruses including hepatitis C, poliovirus, HIV and influenza. Viruses rely heavily on host biosynthesis of glycerolipids, which include phospholipids (PL) and triglycerides (TAG). Importantly, inhibition of this process prevents viral replication. Compounds that target phospholipid biosynthesis will be effective antiviral agents. This approach is especially attractiv because, while virus mutations are likely to produce drug resistance against compounds that target viral structures or processes, this proposal identifies compounds that target a host process, glycerolipid biosynthesis that is critical to viral replication. However, there are very fw known compounds that suppress glycerolipid biosynthesis. To date there have been no high-throughput screening (HTS) protocols available to screen the large number of available compound libraries for inhibitors of animal cell glycerolipid biosynthesis. We propose to develop a cell-based HTS that can be used for this purpose. The proposed photocytotoxic protocol is based upon our previous experience in screening for mutant cell lines deficient in phospholipid or glycerolipid biosynthesis and our extensive experience and knowledge in the area of glycerolipid biosynthesis. Development of such a screening process will allow us to identify small molecules capable of directly or indirectly inhibiting glycerolipid biosynthesis. The availability of such inhibitors will not only be useful in antiviral therapies, but will also yield valuable information about the factors that influence glycerolipid biosynthesis in mammalian cells.
Many viruses require host cell membranes and glycerolipid synthesis for replication, so inhibiting glycerolipid biosynthesis in host animal cells has excellet potential as an effective antiviral strategy. We propose to develop a cell-based protocol that allows for the screening of large libraries of diverse compounds to identify inhibitors of mammalian glycerolipid biosynthesis. Identified compounds will serve as the basis for future development of effective antiviral agents.
| Jarugumilli, Gopala Krishna; Choi, Jong-Ryoul; Chan, PuiYee et al. (2018) Chemical Probe to Identify the Cellular Targets of the Reactive Lipid Metabolite 2- trans-Hexadecenal. ACS Chem Biol 13:1130-1136 |
