High through put screening for small molecules that inhibit the release of enveloped viruses from cells
- 技术优势
- Potentially effective against a large host of pathogenic enveloped viruses because many enveloped viruses use the same mechanism to release particles from cells, including herpes viruses (HSV) , arena- (LFV, LCMV), filo- (EboV, MarV), flavi- (HCV), hepadna- (HBV), rhabdoviruses (VSV, RV), and some paramyxoviruses (SV5, MuV)Increases detection of infected cells by natural immune systemDecreases viral titer in plasma and decelerates the spread of infection Offers a period of time to protect the immune system and clear the infection
- 详细技术说明
- Small molecules that block viral budding from infected cells #therapeutics #smallmolecule #drugdiscovery
- *Abstract
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BACKGROUND
Current HIV treatment involves a cocktail of drugs that target viral entry or virus-specific enzymes. Despite the widespread use of these antivirals, over 1 M were diagnosed with AIDS in the USA in 2011. According to the World Health Organization, 33 M are infected with HIV globally, and 1.8 M die annually. In addition to having strong and undesirable side effects, current drugs are also vulnerable to rapid selection of resistance, requiring newer replacement drugs that act via alternative mechanisms. Northwestern researchers have identified a new class of therapeutics named viral budding inhibitors (VBIs) that target endogenous cellular proteins and may be alternative therapies that are more desirable to current treatments with the potential to become a disruptive new class of antiviral drugs capable of treating numerous enveloped virus infections.
ABSTRACT
VBIs act post-infection, causing viral particles to accumulate on the cell surface and thereby increasing the detection of infected cells by the immune system. Trapped viruses also decrease viral titers, helping slow the spread of infection and offer the body time to fight and clear the infection. By utilizing a novel high throughput strategy, Northwestern researchers identified several compounds that effectively inhibit the viral budding process of enveloped viruses. The investigators used a two-tiered high throughput screening method to detect small molecule compounds to prevent viruses using PTAPP and PPPY L-domain motifs from recruiting the cellular ESCRT proteins that permit them to bud from the cell membrane. The first screen tested potential drug interference with the binding of the viral sequences to either of two cell proteins, Tsg101 and Nedd4. The second screen tested the binding of the drug directly to the cell protein. Compounds that proved positive in the two screens, and were assessed using an HIV model system for additional scrutiny. The data indicate both low and high concentrations of thee assayed small molecules are effective in blocking the budding of infectious retroviruses and lentiviruses in a dose-dependent manner without detectable cytotoxicity.
STATUS OF TECHNOLOGY
Recent data further supports that their compounds inhibit budding of infectious retroviruses and lentiviruses in a dose-dependent manner and without detectable cytotoxicity in culture. Next steps include improving the targeting and performing animal testing.
- *Inventors
- Jonathan Leis*Carol Carter
- *Publications
- Pincetic A and Leis J (2009) TheMechanism of Budding of Retroviruses from Cell Membranes. AdvancedVirology. 2009: 623969.
- 国家/地区
- 美国
