The present application aims to discover multimeric HIV-1 integrase (IN) inhibitors or MINIs. HIV-1 IN multimerization presents an important therapeutic target as the ordered multimeric state is essential for virus replication. The principal objective of our studiesis to impair IN function by stabilizing rather than destabilizing interacting IN subunits to promote aberrant protein multimerization. Our initial proof-of-concept experiments have laid a strong foundation for the feasibility of our approach. We have demonstrated that a small molecule can inhibit IN catalytic activity in vitro by binding at the protein dimer interface, stabilizing the interacting subunits and promoting formation of higher-order oligomers. More recent studies with multifunctional quinoline compounds have demonstrated that these compounds potently target IN multimerization in infected cells. However, the application of quinoline compounds as investigational probes is limited due to the fact that they promote aberrant IN multimerization and inhibit the IN-LEDGF/p75 binding with similar potency. Therefore, new more selective compounds are needed to explore the roles of HIV-1 IN multimerization in the virus life cycle. Accordingly, we propose the following three aims:
Aim 1 will rationally develop MINIs and elucidate their antiviral mechanism of action;
Aim 2 will investigate IN resistance mutations that arise from treatment of HIV-1 in cell culture with MINIs and develop second generation inhibitors;
Aim 3 will focus on discovery of new MINIs through high-throughput screening (HTS) of a library of 365,000 compounds and subsequent hit-to-lead optimization. The proposed studies will develop novel, powerful investigational probes (MINIs) to study HIV-1 molecular biology by selectively targeting IN multimerization. In addition, MINIs are expected to target previously unexploited sites on HIV-1 IN and potently inhibit HIV-1 phenotypes resistant to all currently used HAART. Thus, our studies will facilitate the development of clinically useful new types of allosteric IN inhibitors.

Public Health Relevance

The administration of highly active-antiretroviral therapy (HAART) has enabled what was a terminal disease into a manageable chronic infection. The success of HAART is manifested by reduced mortality and morbidity of HIV-1 infected patients. However, evolution of HIV-1 strains resistant to current therapies is a major clinical problem in the fight against AIDS. Therefore, new inhibitors with novel mechanisms of action are needed. The present application proposes to explore integrase multimerization as a novel therapeutic target and identify multimeric integrase inhibitors that will benefit their development for clinica use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI110310-01A1
Application #
8748522
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gupta, Kailash C
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Pharmacy
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kudryashova, Elena; Koneru, Pratibha C; Kvaratskhelia, Mamuka et al. (2016) Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins. Sci Rep 6:32499
Kessl, Jacques J; Kutluay, Sebla B; Townsend, Dana et al. (2016) HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis. Cell 166:1257-1268.e12
Kessl, Jacques J; Sharma, Amit; Kvaratskhelia, Mamuka (2016) Methods for the Analyses of Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase. Methods Mol Biol 1354:149-64
Pi, Fengmei; Zhao, Zhengyi; Chelikani, Venkata et al. (2016) Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism. J Virol 90:8036-46
Patel, Disha; Antwi, Janet; Koneru, Pratibha C et al. (2016) A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain. J Biol Chem 291:23569-23577
Agharbaoui, Fatima E; Hoyte, Ashley C; Ferro, Stefania et al. (2016) Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase. Eur J Med Chem 123:673-83
Feng, Lei; Dharmarajan, Venkatasubramanian; Serrao, Erik et al. (2016) The Competitive Interplay between Allosteric HIV-1 Integrase Inhibitor BI/D and LEDGF/p75 during the Early Stage of HIV-1 Replication Adversely Affects Inhibitor Potency. ACS Chem Biol 11:1313-21
Feng, Lei; Larue, Ross C; Slaughter, Alison et al. (2015) HIV-1 integrase multimerization as a therapeutic target. Curr Top Microbiol Immunol 389:93-119
Sharma, Amit; Slaughter, Alison; Jena, Nivedita et al. (2014) A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog 10:e1004171
Shkriabai, Nikoloz; Dharmarajan, Venkatasubramanian; Slaughter, Alison et al. (2014) A critical role of the C-terminal segment for allosteric inhibitor-induced aberrant multimerization of HIV-1 integrase. J Biol Chem 289:26430-40

Showing the most recent 10 out of 12 publications