TY  - JOUR
AU  - Lee, HS
AU  - Wang, SH
AU  - Daniel, JT
AU  - Hossain, MA
AU  - Clark, RJ
AU  - Bathgate, RAD
AU  - Rosengren, KJ
Y2  - 2020/11/17
Y1  - 2020/10/01
SN  - 2227-9059
UR  - http://hdl.handle.net/11343/251728
AB  - 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 α-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 α, α'-dibromo-m-xylene. However, in contrast to previously reported dicarba variants, neither were found to promote structure and RXFP3 activity.
LA  - English
PB  - MDPI
T1  - Exploring the Use of Helicogenic Amino Acids for Optimising Single Chain Relaxin-3 Peptide Agonists
DO  - 10.3390/biomedicines8100415
IS  - Biomedicines
VL  - 8
IS  - 10
SP  - 1-16
L1  - /bitstream/handle/11343/251728/PMC7602263.pdf?sequence=1&isAllowed=y
ER  -