Open AccessTuning the Biological Activity of RGD Peptides with Halotryptophans
Author(s) -
Isabell Kemker,
David C. Schröder,
Rebecca C Feiner,
Kristian M. Müller,
Antoine Marion,
Norbert Sewald
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01536
Subject(s) - chemistry , moiety , indole test , selectivity , integrin , combinatorial chemistry , stereochemistry , cyclic peptide , conjugated system , tryptophan , peptide , biochemistry , amino acid , organic chemistry , receptor , polymer , catalysis
An array of l- and d-halotryptophans with different substituents at the indole moiety was synthesized employing either enzymatic halogenation by halogenases or incorporation of haloindoles using tryptophan synthase. Introduction of these Trp derivatives into RGD peptides as a benchmark system was performed to investigate their influence on bioactivity. Halotryptophan-containing RGD peptides display increased affinity toward integrin α v β 3 and enhanced selectivity over integrin α 5 β 1 . In addition, bromotryptophan was exploited as a platform for late-stage diversification by Suzuki-Miyaura cross-coupling (SMC), resulting in new-to-nature biaryl motifs. These peptides show enhanced affinity toward α v β 3 , good affinity to α v β 8 , and remarkable selectivity over α 5 β 1 and α IIb β 3 while featuring fluorogenic properties. Their feasibility as a probe was demonstrated in vitro . Extensive molecular dynamics simulations were undertaken to elucidate NMR and high-performance liquid chromatography (HPLC) data for these late-stage diversified cyclic RGD peptides and to further characterize their conformational preferences.