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The Development of Platforms for Inhibiting RHAMM-HA Interactions & the Development of an Optical Probe for Measuring Glomerular Filtration Rate
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The Development of Platforms for Inhibiting RHAMM-HA Interactions & the Development of an Optical Probe for Measuring Glomerular Filtration Rate
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Dissertation
The Development of Platforms for Inhibiting RHAMM-HA Interactions & the Development of an Optical Probe for Measuring Glomerular Filtration Rate
2018
Overview
Carbohydrates are a class of molecule occurring widely in the body. Their presence has varied biological implications, generating clinical interest regarding their impact on disease prognosis. This thesis will investigate the development of chemical entities surrounding two carbohydrates, hyaluronan and inulin. The Receptor for hyaluronan mediated motility (RHAMM) is one of several receptors for hyaluronan (HA), a polysaccharide that, when fragmented, has pro-angiogenic and inflammatory properties. RHAMM expression is tightly regulated during homeostasis but increases in response to cellular stress, including during injury or disease states. HA-RHAMM interactions stimulate the Ras-ERK-Mek pathway to promote cell motility, differentiation, and proliferation. Specific inhibition of HA-RHAMM interactions could have significant therapeutic potential. Chapters 2 and 3 explore two platforms for disrupting HA-RHAMM interactions. Chapter 2 discusses development of a 62-amino acid chemically synthesized truncated RHAMM protein, 7 kDa RHAMM, for use in screening novel therapeutics. This mini-protein exhibited similar secondary structure, bioactivity, and HA-binding capabilities as the full-length protein, and binds known RHAMM-binding peptides with similar affinities as recombinant RHAMM. This suggests that it is a suitable replacement for the difficult-to-obtain recombinant version. Chapter 3 discusses the development of double stapled RHAMM peptide mimetics as therapeutic anti-inflammatory agents. The peptides were evaluated for secondary structure, HA-binding capability, and inflammation-related bioactivity. The lead compound blocked 27.2% and 52% of induced inflammation in culture and in vivo, respectively. The lead peptide was further optimized to improve metabolic stability while maintaining secondary structure and HA-binding affinity, improving therapeutic efficacy. Glomerular filtration rate (GFR) is a measure of kidney function and a prognostic indicator of chronic kidney disease. Filtration of the polysaccharide inulin is the gold standard for measuring GFR clinically, as it is neither reabsorbed nor secreted by the kidneys; however, this method is laborious and invasive. Chapter 3 explores the development of a near-infrared dye-labeled inulin, Cy7.5-inulin conjugate, as an optical probe to accurately and non-invasively measure GFR by transcutaneous pulse dye densitometer. The conjugate was characterized by different analytical techniques, and is stable under in vivo conditions. The probe was successfully used in a pig model to accurately measure GFR non-invasively.
