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THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS

Antwi, Janet
http://rave.ohiolink.edu/etdc/view?acc_num=osu1500653561243795

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Pharmacy.
In the past quarter century, there has been tremendous progress in the discovery of antiretroviral therapy, making HIV/AIDS a manageable chronic disease. However, the HIV virus is relentless and continues to evolve under drug pressure to escape control and continue infection. The enzyme HIV integrase is responsible for the incorporation of viral double stranded DNA into a host chromosomal DNA and has recently become an attractive target in combating HIV resistance. Raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) are three clinically approved active-site integrase inhibitors. Unfortunately, mutations of the enzyme observed in patients have resulted in resistance to thedrug in the clinic. A new approach to targeting integrase (IN) is the development of allosteric inhibitors that specifically target the protein-protein interaction between IN and its cellular cofactor LEDGF/p75. Recently discovered quinoline-based allosteric integrase inhibitor (ALLINI) B1224436 was the first compound to advance into clinical trials but was discontinued due to poor pharmacokinetic properties including low in vivo clearance. In addition, several reports have revealed the emergence of resistance due to mutation to quinoline based ALLINIs. Applying scaffold hopping approach, several pyridine-based, thiophenes, pyrazoles, isoquinolines and other heteroaromatic cores have been studied as ALLINIs. However to date, there are no clinically approved allosteric IN inhibitors. Herein, I present Fragment Based Approach (FBDD), High Throughput Screen (HTS) and scaffold hopping approaches employed towards the discovery of novel ALLINIs. Chapter 1 discusses the background and significance of HIV infection and introduces HIV-1 IN as a recent drug target. This chapter also focuses on IN structural biology and function and the role of LEDGF/p75 in the viral integration process. Next, it discusses the mechanism of current IN active site inhibitors and the resistance associated with them. Finally, a summary of previously discovered allosteric IN inhibitors targeting the LEDGF/p75 binding site. Chapter 2 presents the HTS approach towards the discovery of novel IN inhibitors. The Scripps Research Institute Molecular Screening Center (SRIMSC) screened an NIH chemical library of 365,000 compounds in an assay provided by our collaborator Dr. Mamuka Kvaratskhelia (The Ohio State University). The primary screen resulted in 2331 hits while the counter screen provided 731 hit compounds. By applying medicinal chemistry structural analysis and hit-to-lead optimization we have discovered a novel piperidine acid with an IC50 of 16.96 µM. In chapter 3, the FBDD effort towards the discovery of allosteric inhibitors was discussed. This project was conducted in collaboration with Dr. Eddy Arnold (Rutgers University). Crystallographic screen of approximately 900 fragments against integrase catalytic core domain (CCD) identified MB36-3 as the lead compound with IC50 greater than 800 µM. Upon synthetic optimization, ethyl-pyrrole derivative MB36-3-5 was the most active with an IC50 of 72 µM in the LEDGF/p75-dependent integrase assay and antiviral activity of EC50 of 36 µM in vitro. It also inhibited IN mutants that confer resistance to quinoline-based compounds. Although these inhibitors are not as potent as current ALLINIs these findings argue strongly for the further development of this new class of compounds for IN inhibition. Chapter 4 describes the scaffold hopping approach which led to the discovery of indole based ALLINIs. The central quinoline core of existing ALLINIs was exchanged for indole while keeping the pharmacophore groups intact. Preliminary data of indole-based ALLINI showed that this class of compounds retained activity against A128T mutant which confers resistance against integrase inhibitors. The most potent compound in this series displayed good activity in the LEDGF/p75 dependent integration assay (IC50 = 4.5 µM). Since then a total of 42 differentially functionalized second generation indole compounds have been synthesized and evaluated in the LEDGF/p75 independent assay. To our delight, 7 of the 42 analogues tested have IC50 below 1µM with the most potent compound having an IC50 of 0.32 µM. Crystal structure analysis confirms that indole-based ALLINIs bind in the LEDGF/p75 site with the key hydrogen bonding interactions previously discovered. Chapter 5 covers the detailed experimental for the synthesis of the HTS, FBDD and indole-based lead compounds and their analogues. It also includes the NMR spectra of selected compound
James Fuchs (Advisor)
267 p.
Chemistry

Recommended Citations

Citations

  • Antwi, J. (2017). THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500653561243795

    APA Style (7th edition)

  • Antwi, Janet. THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1500653561243795.

    MLA Style (8th edition)

  • Antwi, Janet. "THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500653561243795

    Chicago Manual of Style (17th edition)

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