Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity

: Meinander K, Weisell J, Pakkala M, Tadd AC, Hekim C, Kallionpää R, Widell K, Stenman UH, Koistinen H, Närvänen A, Vepsäläinen J, Luthman K, Wallen EAA

Publisher: ROYAL SOC CHEMISTRY

: 2013

: MedChemComm

: MEDCHEMCOMM

: 4

: 3

: 549

: 553

: 5

: 2040-2503

DOI: https://doi.org/10.1039/c3md20292e

Pseudopeptides based on the kallikrein-related peptidase 3 (KLK3) activating bicyclic peptide "C-4" comprising hydrocarbon-based disulphide bridge mimetics have been synthesized. After investigating different synthetic approaches, the pseudopeptides were successfully cyclized from two L-allylglycine side chains via an alkene ring-closing metathesis reaction during the peptide synthesis. The alkene-linker was formed in a 1 : 1 E/Z isomer ratio. The resulting pseudopeptides were almost as potent as the parent peptide, increasing the activity of KLK3 over four-fold at 200 mu g ml(-1) (130-140 mu M) concentrations.