Exploring the Use of Helicogenic Amino Acids for Optimising Single Chain Relaxin-3 Peptide Agonists
| Autor: | James T. Daniel, K. Johan Rosengren, Shu Hui Wang, Richard J. Clark, Ross A. D. Bathgate, Mohammed Akhter Hossain, Han Siean Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
relaxin-3 Medicine (miscellaneous) Peptide 01 natural sciences Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Residue (chemistry) Receptor lcsh:QH301-705.5 chemistry.chemical_classification Relaxin RXFP3 helical stapling 010405 organic chemistry Chemistry Ligand (biochemistry) 0104 chemical sciences Amino acid α-aminoisobutyric acid 030104 developmental biology Biochemistry lcsh:Biology (General) Relaxin-3 Cysteine |
| Zdroj: | Biomedicines, Vol 8, Iss 415, p 415 (2020) Biomedicines Volume 8 Issue 10 |
| ISSN: | 2227-9059 |
| Popis: | Relaxin-3 is a highly conserved two-chain neuropeptide that acts through its endogenous receptor the Relaxin Family Peptide-3 (RXFP3) receptor. The ligand/receptor system is known to modulate several physiological processes, with changes in food intake and anxiety-levels the most well studied in rodent models. Agonist and antagonist analogues based on the native two-chain peptide are costly to synthesise and not ideal drug leads. Since RXFP3 interacting residues are found in the relaxin B-chain only, this has been the focus of analogue development. The B-chain is unstructured without the A-chain support, but in single-chain variants structure can be induced by dicarba-based helical stapling strategies. Here we investigated whether alternative helical inducing strategies also can enhance structure and activity at RXFP3. Combinations of the helix inducing &alpha aminoisobutyric acid (Aib) were incorporated into the sequence of the relaxin-3 B-chain. Aib residues at positions 13, 17 and 18 partially reintroduce helicity and activity of the relaxin-3 B-chain, but other positions are generally not suited for modifications. We identify Thr21 as a putative new receptor contact residue important for RXFP3 binding. Cysteine residues were also incorporated into the sequence and cross-linked with dichloroacetone or &alpha &alpha &rsquo dibromo-m-xylene. However, in contrast to previously reported dicarba variants, neither were found to promote structure and RXFP3 activity. |
| Databáze: | OpenAIRE |
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