title: 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).
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.
authors: Department of Pharmacodynamics, University of Florida , Gainesville, Florida 32610, United States.
authors: Erica M
authors: EM
authors: Haslach
authors: Huisuo
authors: H
authors: Huang
authors: Marvin
authors: M
authors: Dirain
authors: Ginamarie
authors: G
authors: Debevec
authors: Phaedra
authors: P
authors: Geer
authors: Radleigh G
authors: RG
authors: Santos
authors: Marc A
authors: MA
authors: Giulianotti
authors: Clemencia
authors: C
authors: Pinilla
authors: Jon R
authors: JR
authors: Appel
authors: Skye R
authors: SR
authors: Doering
authors: Michael A
authors: MA
authors: Walters
authors: Richard A
authors: RA
authors: Houghten
authors: Carrie
authors: C
authors: Haskell-Luevano
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D062126:Databases, Chemical; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4