Grant: $246,009 - National Institutes of Health - Jul. 23, 2009
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Award Description: Our central hypothesis is that the interaction between HIV-1 integrase (IN) and the cellular co-factor LEDGF/p75 is important for efficient viral replication. We further hypothesize that inhibitors of this interaction have antiviral activity, a low chance of inducing antiviral resistance, and should have low toxicity. Designed drugs targeting an essential IN-cofactor hotspot will have a major impact on current treatment regimens. The IN- LEDGF/p75 disrupting drugs would display synergistic interactions with components of HAART cocktails. Because these designed drugs target spots different from the active site, they would also display synergy with other IN inhibitors presently in development, which target the active site of the enzyme. Patients receiving HAART therapy over long periods often develop drug resistant viral strains. Drugs specific for IN-LEDGF/p75 interactions represent a completely different class of compounds, and target different stages in the viral life cycle. Viral strains exhibiting resistance to reverse transcriptase, protease, or even IN inhibitors would still be susceptible to this class of therapeutics. Additionally, the emergence rate of viral strains resistant to potential IN-LEDGF/p75 disrupting drugs would presumably be considerably slower than that to traditional antiviral therapeutics since the interface includes a cellular protein with much lower genetic variability. The study of IN cofactors and the design of potential IN-cofactor disrupting drugs is an emerging field with the potential for major developments. Previously, we created eukaryotic 293T cell lines stably expressing IN and identified LEDGF/p75 as an important cellular co-factor of IN. Recently, we have developed a high throughput assay to screen for inhibitors of the LEDGF/p75-IN interaction and have identified a series of novel inhibitors. In this proposal our goal is to characterize these inhibitors, especially their interaction with IN, antiviral activity, and design optimized inhibitors selectively blocking their interactions with IN. More specifically we propose: Aim 1. To design novel inhibitors of the LEDGF/p75-IN interaction and Aim 2. To validate our top 10 compounds as bona fide inhibitors of IN-LEDGF/p75 interaction. Successful completion of this study will show that this innovative strategy provides a new target and inhibitor for antiretroviral therapy and for further interrogating the LEDG/p75 pathway. By extension this approach can be exploited in other diseases where protein-protein interactions can be safely inhibited without affecting cellular function. PUBLIC HEALTH RELEVANCE: HIV-1 integrase interacts with a series of cellular co-factors and many of these interactions such as with LEDGF/p75 are important for efficient viral replication. Selective inhibition of these interactions provides a unique strategy to design novel and safe drugs with antiviral activity.
Project Description: Three FTEs are working on the ARRA funded proposal for the total duration of the grant: The PI at 5% effort and a Postdoctoral Research Associate and a Predoctoral student both at 100% efforts. The Postdoctoral Research Associate is trained in computational chemistry and will be responsible for all the design and discovery of the novel inhibitors whereas the Predoctoral Fellow will be responsible for testing of all the compounds in various pharmacological assays. We have weekly meetings to go over the data and to trouble shoot any difficulties we encounter. We also communicate through email and phone with Dr. Debyser, our subcontract laboratory. Our central hypothesis is that the interaction between HIV-1 integrase (IN) and the cellular co-factor LEDGF/p75 is important for efficient viral replication. We further hypothesize that inhibitors of this interaction have antiviral activity, a low chance of inducing antiviral resistance, and should have low toxicity. Our first aim is to design novel inhibitors of the LEDGF/p75-IN interaction. Specifically, we have already begun a high throughput virtual screen of our library of small-molecule compounds using the recently determined 3D structure, PDB 2B4J. We have identified a list of 50 compounds that are potentially interesting. We are testing these compounds in our assays specific to IN as well as in a new assay designed to interrupt the interaction between IN and LEDGF/p75. The best compound will be tested in the laboratory of Dr. Zeger Debyser for antiviral activity. Dr. Debyser is our long time collaborator and together we have been working in this area for over 10 years. Members of our two laboratories have been visiting each other and working in each other?s laboratory and we expect this collaboration will proceed smoothly.
Jobs Summary: Faculty and Investigators, Scientific/ Technical Professionals and Staff (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 23, 2009. Help expand these official descriptions using the wiki below.