Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist

Mark D. Ericson, Skye R. Doering, Courtney M. Larson, Katie T. Freeman, Travis M. Lavoi, Haley M. Donow, Radleigh G. Santos, Rachel H. Cho, Zoe M. Koerperich, Marc A. Giulianotti, Clemencia Pinilla, Richard A. Houghten, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The melanocortin-4 receptor (MC4R) plays an important role in appetite. Agonist ligands that stimulate the MC4R decrease appetite, while antagonist compounds increase food consumption. Herein, a functional mixture-based positional scan identified novel MC4R antagonist sequences. Mixtures comprising a library of 12,960,000 tetrapeptides were screened in the presence and absence of the NDP-MSH agonist. These results led to the synthesis of 48 individual tetrapeptides, of which 40 were screened for functional activity at the melanocortin receptors. Thirteen compounds were found to possess nanomolar antagonist potency at the MC4R, with the general tetrapeptide sequence Ac-Aromatic-Basic-Aromatic-Basic-NH2. The most notable results include the identification of tetrapeptide 48 [COR1-25, Ac-DPhe(pI)-Arg-Nal(2′)-Arg-NH2], an equipotent MC4R antagonist to agouti-related protein [AGRP(86-132)], more potent than miniAGRP(87-120), and possessing 15-fold selectivity for the MC4R versus the MC3R. These tetrapeptides may serve as leads for novel appetite-inducing therapies to treat states of negative energy balance, such as cachexia and anorexia.

Original languageEnglish (US)
Pages (from-to)14860-14875
Number of pages16
JournalJournal of medicinal chemistry
Volume64
Issue number19
DOIs
StatePublished - Oct 14 2021

Bibliographical note

Funding Information:
This work has been supported by NIH Grants R01DK091906 and R01DK124504. R.C. was supported by a 2019 Undergraduate Research Scholarship from the University of Minnesota.

Publisher Copyright:
© 2021 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist'. Together they form a unique fingerprint.

Cite this