BPS 2016
The Discovery of Peptides Targeting RHAMM-HA Interactions
Len Luyt
Associate Professor, University of Western Ontario
ABSTRACT
The interaction of the polysaccharide hyaluronan (HA) with RHAMM (receptor for hyaluronan mediated motility) is implicated in the promotion of inflammatory responses. RHAMM is an intracellular tubulin-binding protein that, in response to injury, is exported to the cell surface, associates with CD44 and, upon binding to HA, results in activation of growth factor signalling pathways, including ERK1,2. Interfering with RHAMM-HA interactions has therapeutic potential for inflammation-related diseases including arthritis, chronic fibrosis and cancer. We have discovered peptides that interfere with RHAMM-HA binding. In one approach, peptides that bind to RHAMM were developed based upon sequences of the carboxy-terminal tail region of tubulins that bind to the RHAMM HA binding region. These peptides act as mimics of HA and it has been shown that they have selectivity for RHAMM over other HA receptors such as CD44. In another approach, stapled peptides consisting solely of the HA binding domain of RHAMM were discovered to maintain the alpha-helical character of RHAMM and bind to HA. The evaluation of these peptides for their effect on cell migration/invasion, inflammation and fibrosis, will be discussed. The ability to discover peptides that interfere in RHAMM-HA interactions sets a precedent for a new approach in the development of drugs that target protein-carbohydrate interactions.
BIO
Dr. Len Luyt received his Ph.D. from the University of Western Ontario in Chemistry and subsequently undertook a post-doctoral fellowship with Prof. John Katzenellenbogen at the University of Illinois, Urbana-Champaign. He then led a research team as a Senior Medicinal Chemist with the pharmaceutical company Bayer-Schering. Dr. Luyt joined Western University in 2005 as a faculty member with a joint appointment in the departments of Oncology, Chemistry and Medical Imaging. He has published 36 journal articles, 5 book chapters, greater than 80 conference abstracts, and has 9 patents granted or applied for. He was awarded the Early Researcher Award (ERA) from the Ministry of Research and Innovation and has held peer-reviewed grant funding from NSERC, CIHR, OICR, Prostate Cancer Canada and the Canadian Breast Cancer Foundation. The research program of Dr. Luyt spans from basic chemistry activities, looking at novel methods of incorporating metal complexes into peptide structures, through to applied research, investigating new peptide therapeutics and molecular imaging agents for novel cancer targets.