Biological Evaluation of Multiple Cyclotide Scaffolds and Other Mimetics at Human Melancortin Receptors

Persistent Link:
http://hdl.handle.net/10150/297492
Title:
Biological Evaluation of Multiple Cyclotide Scaffolds and Other Mimetics at Human Melancortin Receptors
Author:
Bao, Jennifer
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Because of their multiplicity and ubiquity in mammalian systems as central modulators of signaling, GPCRs have held a special interest in drug design. Specifically, ligands targeting the homeostatic class of GPCRs known as melanocortin receptors (MCRs) have the potential to remedy the symptoms of obesity, diabetes, and pain. Adenylate cyclase and binding assays were performed on HEK 293 cells expressing hMC1R, hMC3R, hMC4R, and hMC5R to assess a class of 39 multiple-disulfide, cyclized MSH analogues featuring strategic N-methylation and based on the protein topology of conotoxins found in the venoms of marine cone snails. Because of their potency and selectivity, conotoxins offer a promising avenue for drug design; furthermore, the cyclic backbone and cystine knot motifs of the analogues afforded specific conformational constraining in addition to enhanced proteolytic stability and bioavailability. Several selective compounds were identified from the library with IC₅₀ and EC₅₀ values in the low nanomolar to low micromolar range; these results provide important starting points for optimization. Additionally, two libraries of small molecule mimetics and cyclic peptide analogues synthesized by former group members James Cain and Joel Nyberg were assessed using the same methods; therapeutically relevant selectivity profiles were exhibited by several small molecules in these libraries.
Type:
text; Electronic Thesis
Degree Name:
B.S.
Degree Level:
bachelors
Degree Program:
Honors College; Chemistry & Biochemistry
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor; McEvoy, Megan

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleBiological Evaluation of Multiple Cyclotide Scaffolds and Other Mimetics at Human Melancortin Receptorsen_US
dc.creatorBao, Jenniferen_US
dc.contributor.authorBao, Jenniferen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractBecause of their multiplicity and ubiquity in mammalian systems as central modulators of signaling, GPCRs have held a special interest in drug design. Specifically, ligands targeting the homeostatic class of GPCRs known as melanocortin receptors (MCRs) have the potential to remedy the symptoms of obesity, diabetes, and pain. Adenylate cyclase and binding assays were performed on HEK 293 cells expressing hMC1R, hMC3R, hMC4R, and hMC5R to assess a class of 39 multiple-disulfide, cyclized MSH analogues featuring strategic N-methylation and based on the protein topology of conotoxins found in the venoms of marine cone snails. Because of their potency and selectivity, conotoxins offer a promising avenue for drug design; furthermore, the cyclic backbone and cystine knot motifs of the analogues afforded specific conformational constraining in addition to enhanced proteolytic stability and bioavailability. Several selective compounds were identified from the library with IC₅₀ and EC₅₀ values in the low nanomolar to low micromolar range; these results provide important starting points for optimization. Additionally, two libraries of small molecule mimetics and cyclic peptide analogues synthesized by former group members James Cain and Joel Nyberg were assessed using the same methods; therapeutically relevant selectivity profiles were exhibited by several small molecules in these libraries.en_US
dc.typetexten_US
dc.typeElectronic Thesisen_US
thesis.degree.nameB.S.en_US
thesis.degree.levelbachelorsen_US
thesis.degree.disciplineHonors Collegeen_US
thesis.degree.disciplineChemistry & Biochemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor-
dc.contributor.advisorMcEvoy, Megan-
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