Development of Selective Peptide Ligands Targeting Melanocortin Receptors for Melanoma Prevention and Therapy
AdvisorHruby, Victor J.
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PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
EmbargoRelease after 02/21/2021
AbstractMelanocortin receptors are a family of G-protein-coupled receptors (GPCRs) that regulate many important physiological functions. Specifically, melanocortin-1-receptor (MC1R) on skin melanocytes regulates skin pigmentation, which is a natural protection against UV-induced DNA damage, the major risk for melanoma. However, the lack of selectivity to MC1R and the requirements of needle injections of currently available peptide drugs greatly hinder the development of MC1R agonists as melanoma prevention medicines. This thesis mainly describes efforts to develop MC1R selective peptide agonists. Inspired by previous structure-activity studies and receptor mutagenesis studies, the peptide drug design enhances MC1R selectivity through removing strong ionic interactions between ligand and melanocortin receptors other than MC1R, introducing local structural constrains on the backbone (N-methylations) and sidechain (φ and ψ angle constrains) as well as global conformational constrains on cyclic peptides. The other emphasis of this thesis is to develop peptide drugs that are accessible to the target receptors and can be taken in a non-invasive way. To achieve this goal, different peptide drug design templates were exploited. Lead compounds with potentials for different applications include: 1. a long linear peptide suitable to be directly applied to the skin surface and induce skin pigmentation with less concerns on side effects; 2. tetrapeptides with great potential to be developed into oral administration drugs to induce skin pigmentation; 3. cyclic peptides suitable to target the MC3R or the MC4R in the brain; 4. an orally available cyclotide to activate the MC1R. This thesis also describes the opportunity to target MC1R-overexpressing melanoma cells with MC1R agonist for targeted drug delivery. Such approach can bring versatility to the cytotoxic drug selection, which is the key to solve the serious drug resistance problem of melanoma. Future opportunities exist to develop peptide drugs targeting different signaling pathways downstream of melanocortin receptors to regulate physiological functions governed by the same melanocortin receptor subtype.
Degree ProgramGraduate College