Tuning the Biological Activity of RGD Peptides with Halotryptophans

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 αvβ3 and enhanced
selectivity over integrin α5β1.
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 αvβ3, good affinity to αvβ8, and remarkable selectivity over α5β1 and αIIbβ3 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.