Revealing the Indispensable Role of the RFamide Functionality using a Novel Acid Labile Benzofuranone based Amine (ALBA) Linker

The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C‐terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated,...

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Bibliographic Details
Published inHelvetica chimica acta Vol. 107; no. 4
Main Authors Mudd, Gemma, Hendrikse, Megan, Shave, Steven, Houston, Douglas R, Millar, Robert P, Auer, Manfred
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 01.04.2024
Wiley Subscription Services, Inc
Subjects
Amines
Benzoic acid
Chemistry
Chemistry, Multidisciplinary
cleavable linker
G protein-coupled receptors
GPCR
GPR54
Kiss1 protein
Kisspeptin
Ligands
Neuropeptides
Peptide synthesis
Peptides
Physical Sciences
Protein synthesis
Receptor mechanisms
RFamide
Science & Technology
solid phase peptide synthesis (SPPS)
Solid phases
MIMETICS
SOLID-PHASE SYNTHESIS
KISS-1
GPR54
Kisspeptin
PEPTIDES
PROTECTING GROUP
PROTEIN-COUPLED RECEPTOR
cleavable linker
RFamide
GPCR
INHIBITORS
LIGAND
solid phase peptide synthesis (SPPS)
EFFICIENT
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Summary:The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C‐terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5‐(3‐aminopropylcarbamoyl)‐2‐[[tert‐butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine‐containing analogue revealed that the group is not compatible with receptor activation.
ISSN:0018-019X
1522-2675
DOI:10.1002/hlca.202300204