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The Design, Synthesis and Optimization of Allosteric Hiv-1

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The Design, Synthesis and Optimization of Allosteric Hiv-1 THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Janet Antwi Graduate Program in Pharmaceutical Sciences The Ohio State University 2017 Dissertation Committee: Professor James R. Fuchs, Advisor Professor Werner Tjarks Professor Karl A. Werbovetz Copyright by Janet Antwi 2017 Abstract 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, ii 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 iii 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 iv Dedication This book is dedicated to my entire family for their unfailing love, support and encouragement especially my parents. Thank you. v Acknowledgments First and foremost I would like to thank God for how far He has brought me. I want to use this opportunity to say a big thank you to my advisor Dr. James Fuchs for accepting me into his research group and for the constant support and advice throughout graduate school. Under his guidance, I have become a refined organic chemist and an excellent public speaker. In addition to chemistry, I have learnt a lot from his presentation and teaching style that I hope to apply in my career. Secondly, I would like to thank my research committee members Dr. Karl Werbovetz, Dr. Werner Tjarks and Dr. Chenglong Li. for taking time to read my thesis and for all the research suggestions throughout the years. I thank all past and present members of the Fuchs lab especially Dr. Nivedita Jena and Dr. Pratiq Patel for their contribution towards the HIV project. I thank my colleagues Chido Hambira, Andrew Hutsman, Tyler Wilson, BoTokarski, Yara Mansour, Bernadette Latimer, Nick Cockroft and Dr. Daniel Adu-Ampratwum for constantly challenging me to be a better scientist and for making our lab, an enjoyable second home. I will always remember all the challenges we faced and all the laughter we shared together. vi My dissertation work would not have been as successful without our collaborators Dr. Mamuka Kvaratskhelia and Dr. Eddy Arnold and members of their labs especially Disha Patel, Pratibha Koneru and Matt Kobe. Our collaborators provided all the x-ray crystallography data and biological data for the compounds synthesized for this project. I thank the Director of instrumentation Dr. Craig McElroy for NMR, Mass Spec and HLPC training and constant support and guidance. I would not be here today without the constant love, encouragement and prayer support from my family members especially my parents. My parents sacrificed a lot for me to come to the United States to pursue my dreams and for that, I am eternally grateful. I want to thank my god parents Rev. and Mrs. Abosi for their prayers, advice and constant motivation all these years. My mentors Mr. and Mrs. Paintsil have been there for me in diverse ways and I thank them for everything they have lost on my behalf. I thank my church family especially my friend in the Voices of Glory choir (The Church of Pentecost USA Inc). Singing in this choir, was the perfect outlet I needed to complete this doctoral degree. Last but certainly not the least, I want to thank my husband Derrick Kankam Antwi for his constant love, support and encouragement throughout this process. Thank you for taking care of our beautiful daughter Lisa Pokuah Antwi while I was gone most nights and weekends completing my dissertation work. I could not have done it without you. I also want to thank my daughter Lisa for adding so much joy and purpose to my life and for being a great motivator in ways unknown to her. It really took a nation to raise me to the woman I am today and I am forever indebted to everyone who contributed to my life from childhood until today. vii Vita 2011................................................................ B.A. Chemistry, Binghamton University 2011-2014 ..................................................... Graduate Teaching Associate, Department of Medicinal Chemistry, The Ohio State University 2013-2017 ..................................................... Graduate Research Associate, Department of Medicinal Chemistry, The Ohio State University Publications 1. Patel, D., Antwi, J., Koneru, P., Serrao, E., Forli, S., Kessl, J., Feng, L., Deng, N., Levy, R., Fuchs, J., Olson, A., Engelman, A., Bauman, J., Kavartskhelia, M., Arnold, E. A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening catalytic core domain J. Biol. Chem.,2016, 45, 23569-23577 viii 2. Patel, P., Kvaratskhelia, N., Mansour, Y., Antwi, J., Feng, L., Koneru, P., Kobe, M., Jena, N., Shi, G., Mosaad. S., Li, C., Kessl., J., Fuchs, J. Indole-based Allosteric Inhibitors of HIV-1 Integrase. Bioorg Med Chem Lett., 2016, 19, 4748-4752 3. Kumar, A., Drozd, M., Pina-Mimbela, R., Xu, X., Mohamed, R., Antwi, J., Fuchs, J., Nislow, C., Templeton, J., Blackall, P., Rajashekara, G. Novel anti- campylobacter compounds identified using high throughput screening of a preselected enriched small molecules library. Frontiers in Microbiology, 2016, 7, 405 4. Ngoje, G., Addae,
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