Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)

Authors

Erica M. Haslach, University of Florida
Huisuo Huang, University of Minnesota
Marvin Dirain, University of Florida
Ginamarie Debevec, Torrey Pines Institute for Molecular Studies
Phaedra Geer, Torrey Pines Institute for Molecular Studies
Radleigh Santos, Torrey Pines Institute for Molecular StudiesFollow
Marc Giulianotti, Torrey Pines Institute for Molecular Studies
Clemencia Pinilla, Torrey Pines Institute for Molecular Studies
Jon R. Appel, Torrey Pines Institute for Molecular Studies
Skye R. Doering, University of Minnesota
Michael A. Walters, University of Minnesota
Richard A. Houghten, Torrey Pines Institute for Molecular Studies
Carrie Haskell-Luevano, University of Minnesota; University of Florida

Document Type

Article

Publication Date

2-11-2014

Publication Title

Journal of Medicinal Chemistry

ISSN

0022-2623

Volume

57

Issue/No.

11

First Page

4615

Last Page

4628

Abstract

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies.

Comments

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

NSUWorks Citation

Haslach, Erica M.; Huang, Huisuo; Dirain, Marvin; Debevec, Ginamarie; Geer, Phaedra; Santos, Radleigh; Giulianotti, Marc; Pinilla, Clemencia; Appel, Jon R.; Doering, Skye R.; Walters, Michael A.; Houghten, Richard A.; and Haskell-Luevano, Carrie, "Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)" (2014). Mathematics Faculty Articles. 232.
https://nsuworks.nova.edu/math_facarticles/232

DOI

10.1021/jm500064t