Design and Synthesis of Hyaluronan:RHAMM Interaction Inhibitors

A major component of the extracellular matrix is hyaluronan, a regulator of cell migration/survival and differentiation during response-to-injury processes. The receptor for hyaluronan-mediated motility (RHAMM) binds to HA and has limited constitutive expression but is upregulated during tissue injury. Blocking HA fragment:RHAMM interactions has therapeutic potential for treating cancer but truncation of RHAMM into peptides mimicking only the HA binding domains is predicted to lose their natural α-helical structure. The goal of this project is to explore the effects cyclizing each binding domain has on helicity and its biological effect. Eighteen peptides were synthesized and cyclized using lactam bridges. The peptides were analyzed by circular dichroism spectroscopy and one stapled peptide exhibited a 4-fold increase in helicity compared to the unstapled sequence and significantly decreased migration, inflammation, and fibrosis in vitro. This cyclic peptide is a novel protein-carbohydrate inhibitor and has the potential to be a therapeutic in the cancer treatment.

Name thesis:degree_name

M Sc

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

The University of Western Ontario

Year dc:date.issued

2017

Author dc:creator

• Rodrigues, Emily

Advisor dc:contributor.advisor

• Len Luyt

• Peptide
• cyclization
• alpha helix
• receptor for hyaluronan mediated motility
• hyaluronan
• cancer

Language dc:language.iso

en_ca

Handle dc:identifier.uri

https://hdl.handle.net/20.500.14721/27538

OAI identifier oai:identifier

oai:uwo.scholaris.ca:20.500.14721/27538