Tuning the Biological Activity of RGD Peptides with Halotryptophanst

Kemker I., Schroeder D. C., Feiner R. C., Mueller K. M., MARION A., Sewald N.

JOURNAL OF MEDICINAL CHEMISTRY, vol.64, no.1, pp.586-601, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 64 Issue: 1
  • Publication Date: 2021
  • Doi Number: 10.1021/acs.jmedchem.0c01536
  • Journal Name: JOURNAL OF MEDICINAL CHEMISTRY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.586-601
  • Middle East Technical University Affiliated: Yes

Abstract

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 alpha(nu)beta(3) and enhanced selectivity over integrin alpha(5)beta(1). In addition, bromotryptophan was exploited as a platform for latestage diversification by Suzuki-Miyaura cross-coupling (SMC), resulting in new-to-nature biaryl motifs. These peptides show enhanced affinity toward alpha(nu)beta(3), good affinity to alpha(nu)beta(8), and remarkable selectivity over alpha(5)beta(1) and alpha(IIb)beta(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.