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Peptoid NPhe4 in AGRP-Based c[Pro1‑Arg2‑Phe3‑Phe4‑Xxx5‑Ala6‑Phe7‑DPro8] Scaffolds Maintain Mouse MC4R Antagonist Potency
journal contribution
posted on 2020-04-01, 11:44 authored by Mark D. Ericson, Katie T. Freeman, Carrie Haskell-LuevanoThe
melanocortin receptors are involved in numerous physiological
functions and are regulated by agonists derived from the proopiomelanocortin
gene transcript and two endogenous antagonists, agouti and agouti-related
protein (AGRP). The key binding and functional determinant of AGRP,
an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence
located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop.
It has previously been observed that cyclizing this sequence through
a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist
activity, with increased MC4R potency when a diaminopropionic acid
(Dap) residue is substituted at position 5. In this report, a series
of 11 single-peptoid substitutions were performed in the AGRP-derived
macrocycles. While most peptoid substitutions decreased MC4R antagonist
potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist
activity equipotent to the parent scaffolds. These data may be used
in the design of future MC4R and MC5R antagonist leads and probes
that possess increased metabolic stability due to the presence of
peptoid residues.
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compound 7MC 4R antagonist potencyNPhe 4Arg 2parent scaffolds11 single-peptoid substitutionsAsn 5MC 4R potencyNDab 5DPro-Pro motifMC 4R antagonist activityPhe 3Phe 4Phe 7Arg-Phe-Phe tripeptide sequenceMC 3Rfuture MC 4RMC 4R antagonistdiaminobutyric acidagouti-related proteinagonist activitypeptoid substitutionsMouse MC 4R Antagonist PotencyAGRP-derived macrocyclescompounds 4MC 5R antagonistmelanocortin receptorsproopiomelanocortin gene transcriptposition 5.Peptoid NPhe 4NPhe 4 substitutionspeptoid residuesAla 6diaminopropionic acidmacrocyclic scaffold
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