Dataset Information

Incorporation of Agouti-Related Protein (AgRP) Human Single Nucleotide Polymorphisms (SNPs) in the AgRP-Derived Macrocyclic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Decreases Melanocortin-4 Receptor Antagonist Potency and Results in the Discovery of Melanocortin-5 Receptor Antagonists.

ABSTRACT: While the melanocortin receptors (MCRs) are known to be involved in numerous biological pathways, the potential roles of the MC5R have not been clearly elucidated in humans. Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains an exposed ?-hairpin loop composed of six residues (Arg-Phe-Phe-Asn-Ala-Phe) that is imperative for binding and function. Within this active loop of AgRP, four human missense polymorphisms were deposited into the NIH Variation Viewer database. These polymorphisms, Arg111Cys, Arg111His, Phe112Tyr, and Ala115Val (AgRP full-length numbering), were incorporated into the peptide macrocycles c[Pro¹-Arg²-Phe³-Phe⁴-Xaa⁵-Ala⁶-Phe⁷-dPro⁸], where Xaa was Dap⁵ or Asn⁵, to explore the functional effects of these naturally occurring substitutions in a simplified AgRP scaffold. All peptides lowered potency at least 10-fold in a cAMP accumulation assay compared to the parent sequences at the MC4Rs. Compounds MDE 6-82-3c, ZMK 2-82, MDE 6-82-1c, ZMK 2-85, and ZMK 2-112 are also the first AgRP-based chemotypes that antagonize the MC5R.

SUBMITTER: Koerperich ZM

PROVIDER: S-EPMC7250496 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Incorporation of Agouti-Related Protein (AgRP) Human Single Nucleotide Polymorphisms (SNPs) in the AgRP-Derived Macrocyclic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Decreases Melanocortin-4 Receptor Antagonist Potency and Results in the Discovery of Melanocortin-5 Receptor Antagonists.

Koerperich Zoe M ZM Ericson Mark D MD Freeman Katie T KT Speth Robert C RC Pogozheva Irina D ID Mosberg Henry I HI Haskell-Luevano Carrie C

Journal of medicinal chemistry 20200106 5

While the melanocortin receptors (MCRs) are known to be involved in numerous biological pathways, the potential roles of the MC5R have not been clearly elucidated in humans. Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains an exposed β-hairpin loop composed of six residues (Arg-Phe-Phe-Asn-Ala-Phe) that is imperative for binding and function. Within this active loop of AgRP, four human missense polymorphisms were deposited into the NIH Variation Viewer da ...[more]

PMID: 31845801

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Project description:The Agouti-like peptides including AgRP, ASIP and the teleost-specific A2 (ASIP2 and AgRP2) peptides have potent and diverse functional roles in feeding, pigmentation and background adaptation mechanisms. There are contradictory theories about the evolution of the Agouti-like peptide family as well the nomenclature. Here we performed comprehensive mining and annotation of vertebrate Agouti-like sequences. We identified A2 sequences from salmon, trout, seabass, cod, cichlid, tilapia, gilt-headed sea bream, Antarctic toothfish, rainbow smelt, common carp, channel catfish and interestingly also in lobe-finned fish. Moreover, we surprisingly found eight novel homologues from the kingdom of arthropods and three from fungi, some sharing the characteristic C-x(6)-C-C motif which are present in the Agouti-like sequences, as well as approximate sequence length (130 amino acids), positioning of the motif sequence and sharing of exon-intron structures that are similar to the other Agouti-like peptides providing further support for the common origin of these sequences. Phylogenetic analysis shows that the AgRP sequences cluster basally in the tree, suggesting that these sequences split from a cluster containing both the ASIP and the A2 sequences. We also used a novel approach to determine the statistical evidence for synteny, a sinusoidal Hough transform pattern recognition technique. Our analysis shows that the teleost AgRP2 resides in a chromosomal region that has synteny with Hsa 8, but we found no convincing synteny between the regions that A2, AgRP and ASIP reside in, which would support that the Agouti-like peptides were formed by whole genome tetraplodization events. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is the most distantly related to the three other members of that group, first splitting from a common ancestor to ASIP and A2, and then later the A2 split from ASIP followed by a split resulting in ASIP2 and AgRP2.

Dataset Information

Incorporation of Agouti-Related Protein (AgRP) Human Single Nucleotide Polymorphisms (SNPs) in the AgRP-Derived Macrocyclic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Decreases Melanocortin-4 Receptor Antagonist Potency and Results in the Discovery of Melanocortin-5 Receptor Antagonists.

Publications

Incorporation of Agouti-Related Protein (AgRP) Human Single Nucleotide Polymorphisms (SNPs) in the AgRP-Derived Macrocyclic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Decreases Melanocortin-4 Receptor Antagonist Potency and Results in the Discovery of Melanocortin-5 Receptor Antagonists.

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