Tuning the Biological Activity of RGD Peptides with Halotryptophanst

Date

2021-01-01

Author

Kemker, Isabell
Schroeder, David C.
Feiner, Rebecca C.
Mueller, Kristian M.
Marıon, Antoıne
Sewald, Norbert

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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.

URI

https://hdl.handle.net/11511/89309

Journal

JOURNAL OF MEDICINAL CHEMISTRY

DOI

https://doi.org/10.1021/acs.jmedchem.0c01536

Collections

Department of Chemistry, Article

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Citation Formats

I. Kemker, D. C. Schroeder, R. C. Feiner, K. M. Mueller, A. Marıon, and N. Sewald, “Tuning the Biological Activity of RGD Peptides with Halotryptophanst,” JOURNAL OF MEDICINAL CHEMISTRY, pp. 586–601, 2021, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/89309.