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Developing Synthetic Peptide-Based Inhibitors of Human Growth Hormone Receptor

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Developing Synthetic Peptide-Based Inhibitors of Human Growth Hormone Receptor Developing Synthetic Peptide-Based Inhibitors of Human Growth Hormone Receptor A Thesis Presented to The Honors Tutorial College Ohio University In Partial Fulfillment of the Requirements for Graduation from the Honors Tutorial College with the degree of Bachelor of Science in Chemistry by Maya R. Sattler May 2018 2 Acknowledgements This thesis represents the work a large number of people, to whom I am incredibly grateful. Thank you first and foremost to my adviser, Dr. Justin Holub, whose patience and teaching has been outstanding for the entire three years I have worked with him and been his student, all the way to the final deadline. Thank you to Dr. John Kopchick for allowing me the opportunity to explore a different area of research and a different laboratory environment. Both Dr. Lauren McMills and Dean Cary Frith have offered wonderful support and guidance through my entire HTC career and I will forever be appreciative. There are also many fellow students that have helped me with work and encouragement. Thank you to my fellow students in the Holub laboratory, especially Najah Alqaeisoom who was my first teacher and a delight to work with, and Danushka Arachchige who was always willing to help, no matter the problem. I would also like to thank my colleagues at Edison Biotechnology Institute for their support in all things trivial and otherwise. Dr. Reetobrata Basu in particular made all of the cell work possible through his teaching, assistance, and reassurances. Lastly, I am grateful to a larger community of people in Athens and worldwide that helped me through my four years of undergraduate studies and will continue to support me as I continue to progress. 3 Table of Contents Abstract 4 1. Introduction 1.1 Biology of hGH and GHR 5 1.2 Clinical Relevance 8 1.3 Inhibition of hGH Signaling 11 1.4 Peptide design 13 1.5 Scanning Alanine Library 17 1.6 Project Rationale 19 2. Materials and Methods 2.1 Reagents and Chemicals 21 2.2 Peptide Production and Characterization 22 2.3 Biological Assays 27 3. Results and Discussion 3.1 Peptide Production and Characterization 30 3. 2 Biological Assays 32 4. Conclusions 41 References 43 Appendices A. MS Spectra 52 B. Analytical Spectra 57 C. CD Spectra 63 4 Abstract The human growth hormone (hGH) is an important endocrine mediator throughout life with myriad effects and receptors in every tissue of the body and therefore an excess of hGH signaling can negatively impact health. This thesis covers the development of peptide-based mimetics of hGH site 1 that are designed to antagonize the growth hormone receptor (GHR) and inhibit hGH signaling via the Stat5 pathway. In order to investigate the contributions of individual amino acid residues on hGH•GHR interaction, a control peptide and ten peptides that differed by one substitution from the control were synthesized, purified, tested for helical propensity, and screened for hGH signaling inhibition. A comparison of the residues in contact with GHR, the helical propensity, and the biological activity indicated that the ability to form a helix was more important to the inhibitory function of the peptides than was the presence of residues that make direct contact with the GHR. Further development of these peptide-based chemical genetic agents could offer new insights into the fundamental nature of hGH•GHR interactions and improve upon existing therapeutics. 5 1. Introduction 1.1 Biology of hGH and GHR Human growth hormone (hGH) is a 22 kDa single-chain peptide hormone with 191 amino acid residues produced in the anterior pituitary gland.1 Its structure consists of a four-helical bundle with an unusual up-up-down-down connectivity and two disulfide linkages.2 Growth hormone signaling is mediated through the binding of hGH with the growth hormone receptor (GHR), a 28 kDa transmembrane protein in the class I cytokine receptor family. One molecule of hGH binds to two molecules of GHR, which exist as homodimers on the cellular surface even prior to ligand binding.3 The structure of hGH bound to two GHRs can be seen in Figure 1.1 A. There are two distinct binding sites on hGH; site 1 is mainly formed by the A and D helices, whereas site 2 is mainly formed by the A and C helices (Figure 1.1 B).4 The hGH binds sequentially to two overlapping sites on GHR. Site 1 of the hormone binds to the first receptor, followed by subsequent binding of site 2 to the second receptor. This binding provides the driving energy for the change in the relation between the helices of the transmembrane domains of the receptors.5 Upon binding, the helices rotate from a parallel state to a left-handed crossover state, which in turn changes the arrangement between the cytoplasmic domains of the receptor. 6 Figure 1.1. A. hGH (pink) bound to two GHR (purple). Adapted from PDB 1HWG. B. hGH structure with labeled helices. Adapted from PDB 1HGU. The conformational changes in GHR associated with hGH binding initiate an intracellular signaling cascade that begins with the tyrosine kinase, Janus kinase 2 (JAK2).3,5 The GHR lacks intrinsic kinase activity but it binds JAK2 at a proline-rich motif known as Box 1 in its cytoplasmic intracellular domain, close to the cell membrane.6 When the cytoplasmic domains move apart from each other, the pseudokinase inhibitory domain of each JAK2 slides away from the kinase domain of the other JAK2, allowing them to activate each other. This initiates cross-phosphorylation of key tyrosine residues on the GHRs, allowing other molecules to dock and be phosphorylated by JAK2. JAK2 has the potential to activate a number of pathways including the mitogen-activated protein kinase (MAPK) pathway and the Akt/phosphoinositide 3-kinase (PI3K) pathway. However, the primary route of action is through family of gene transcription factors called Signal Transducers and Activators of Transcription (STATs), which has seven members. STAT1, STAT3, and STAT5 are 7 activated by JAK2, but STAT5 in particular mediates the majority of the genomic effects of hGH, such as cell proliferation. Two isoforms, STAT5a and STAT5b, exist and form a dimer when phosphorylated, which translocates to the nucleus to modulate target gene expression. The presence of phosphorylated STAT5 can be used as an indicator of hGH signaling.7 The most notable target of STAT5 activation is the gene encoding insulin-like growth factor 1 (IGF-I), a protein so integral to hGH action that its effects are credited not solely to hGH, but to the hGH/IGF-I axis.8 IGF-I is produced in many tissues in the body where it exerts local effects as an auto- and paracrine hormone. However, liver production of IGF-I is particularly important because the hormone produced there acts as an endocrine signal, having broad-spectrum effects throughout the body.9 One effect is to inhibit the production of hGH from the anterior pituitary, acting as part of a negative feedback cycle that stops its own production. Though hGH and IGF-I production are interdependent, they act in synergistic but independent ways to produce their effect. Receptors for both hGH and IGF-I are present in a wide variety of tissues and thus they have myriad important effects.3 The growth effect for which this hormone axis is most well known is achieved through bone growth and mediated through paracrine IGF-I in the bone plate. The effect of the hGH/IGF-I axis in muscle is to promote protein synthesis and positive nitrogen balance, which leads to an increase in muscle and thus, lean body weight.9 Further contributing to a change in body composition, the hormone axis promotes lipolysis, or the breakdown of fatty acids in adipose tissue, and inhibits lipogenesis, the formation of fatty acids.6 Other effects on adipose tissue include control over preadipocyte proliferation, differentiation, and senescence, and altering levels of 8 adipokines, the hormones released only adipose fat tissue. This axis also affects the critical metabolic hormone, insulin. While hGH promotes insulin resistance10, IGF-I has some insulin-like activity, which could be explained in part by the structural and functional homology between IGF-I and insulin and the IGF-I receptor and insulin receptor.11 1.2 Clinical Relevance Because growth hormone is implicated in not only growth, but also metabolism and endocrine signaling, abnormal levels of hGH in the body can have serious physiological and pathological ramifications. Acromegaly and gigantism are two related conditions caused by an excess of hGH activity, usually due to excess hGH secretion from a pituitary adenoma, a type of tumor in the gland that produces hGH.12 Gigantism results from hypersecretion of hGH in childhood, before the fusion of the epiphyseal growth plates, and is most prominently characterized by excessive growth.13 Acromegaly is a similar condition in adulthood, characterized by excessive growth of organs and tissues, including skeletal tissue. The long-term exposure of hGH and IGF-I resulting from untreated acromegaly is associated with numerous detrimental effects, including arthritis, cardiomyopathy, hypertension, arrhythmias, insulin resistance, diabetes, sleep apnea, and renal failure.12 Furthermore, metabolic, respiratory, and cardio- or cerebrovascular comorbidities contribute to an increase in standardized mortality rates by a factor of two and a decrease in life expectancy by ten years. Acromegaly provides a clear illustration of the adverse health effects of excess hGH, but such severe deviations in hGH levels are not needed for the manifestation of 9 these effects. For example, growth hormone has well-documented diabetogenic activity.10,11,14 The IGF-I produced via hGH signaling can mimic insulin action due to its homology with insulin.
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