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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI081610-02
Application #
7897668
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Gupta, Kailash C
Project Start
2009-07-23
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$204,000
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Serrao, Erik; Wang, Chia-Hao; Frederick, Toinette et al. (2014) Alteration of select gene expression patterns in individuals infected with HIV-1. J Med Virol 86:678-86
Li, Bo-Wen; Zhang, Feng-Hua; Serrao, Erik et al. (2014) Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75. Bioorg Med Chem 22:3146-58
Zhang, Daoguang; Debnath, Bikash; Yu, Shenghui et al. (2014) Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase. Bioorg Med Chem 22:5446-53
Long, Ya-Qiu; Huang, Shao-Xu; Zawahir, Zahrah et al. (2013) Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors. J Med Chem 56:5601-12
Serrao, Erik; Debnath, Bikash; Otake, Hiroyuki et al. (2013) Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction. J Med Chem 56:2311-22
Serrao, Erik; Xu, Zhong-Liang; Debnath, Bikash et al. (2013) Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction. Bioorg Med Chem 21:5963-72
Sanchez, Tino Wilson; Debnath, Bikash; Christ, Frauke et al. (2013) Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions. Bioorg Med Chem 21:957-63
Serrao, Erik; Thys, Wannes; Demeulemeester, Jonas et al. (2012) A symmetric region of the HIV-1 integrase dimerization interface is essential for viral replication. PLoS One 7:e45177
Al-Mawsawi, Laith Q; Neamati, Nouri (2011) Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem 6:228-41
Fan, Xing; Zhang, Feng-Hua; Al-Safi, Rasha I et al. (2011) Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups. Bioorg Med Chem 19:4935-52