Revealing the indispensable role of the RFamide functionality using a novel acid labile benzofuranone based amine (ALBA) linker

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Authors

Mudd, Gemma
Hendrikse, Megan
Shave, Steven
Houston, Douglas R.
Millar, Robert P.
Auer, Manfred

Journal Title

Journal ISSN

Volume Title

Publisher

Wiley

Abstract

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.

Description

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request.
This article also appears in: Andrea Vasella 80th Birthday Biochemistry and Medicinal Chemistry Organic and Organometallic Chemistry.

Keywords

Cleavable linker, Kisspeptin, GPR54, G-protein coupled receptor (GPCR), RFamide, Solid phase peptide synthesis (SPPS), Acid labile benzofuranone based amine (ALBA), SDG-03: Good health and well-being

Sustainable Development Goals

SDG-03:Good heatlh and well-being

Citation

Mudd, G., Hendrikse, M., Shave, S. et al. 2024, 'Revealing the indispensable role of the RFamide functionality using a novel acid labile benzofuranone based amine (ALBA) linker', Helvetica Chimica Acta, vol. 107, no. 4, art. e202300204, pp. 1-7, doi : 10.1002/hlca.202300204.