Halogenated Tryptophans Improve Integrin αVβ6 Affinity of Cyclic RGD Peptides and Provide Handles for Late‐Stage Derivatization
- 1Organic and Bioorganic Chemistry, Faculty of Chemistry Bielefeld University, Universitätsstraße 25 Bielefeld Deutschland
Abstract
Selective targeting of integrin αVβ6 is of high relevance for molecular imaging and therapeutic applications, yet ligands combining high affinity with structural and functional versatility remain limited. A structure–activity relationship (SAR) study of the nonapeptide cyclo‐(‐Asp‐Leu‐Ala‐Phe‐d‐Pro‐NMeLys‐Phe‐Arg‐Gly‐) was performed through site‐specific substitution of phenylalanine residues by tryptophan and halogenated tryptophan derivatives, revealing a pronounced position‐dependent effect on integrin recognition. Substitution at position i+3 relative to the RGD sequence with halotryptophans is identified as an affinity hotspot, enabling picomolar binding to αVβ6. In contrast, modification at position i+6 preserves high αVβ6 affinity while providing exceptional tolerance toward structural diversification and enabling late‐stage functionalization of unprotected peptides via palladium‐catalyzed cross‐coupling reactions. This establishes i+6 modification as a versatile platform for chemoselective derivatization without compromising affinity. Halotryptophans serve both as pharmacophores and synthetic handles. Notably, an anthracenyl‐functionalized derivative combines sub‐nanomolar αVβ6 affinity with water solubility and intrinsic fluorescence, demonstrating that even bulky π‐systems can be accommodated at discrete positions without loss of potency. These integrin ligands are compatible with cellular applications and enable receptor‐specific detection by flow cytometry (FACS) as well as visualization by confocal fluorescence microscopy. This work defines a robust design for αVβ6‐targeting functional probes for molecular imaging and fluorescence‐guided tumor detection.
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BibTeX
@article{nachtigall2026halogenated,
title = {{Halogenated Tryptophans Improve Integrin αVβ6 Affinity of Cyclic RGD Peptides and Provide Handles for Late‐Stage Derivatization}},
author = {Beate Nachtigall and Caroline Brinkmann and Jana Langosch and Anke Nieß and Norbert Sewald},
journal = {Chemistry (Weinheim an Der Bergstrasse, Germany)},
year = {2026},
month = aug,
doi = {10.1002/chem.71559},
url = {https://doi.org/10.1002/chem.71559},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Halogenated Tryptophans Improve Integrin αVβ6 Affinity of Cyclic RGD Peptides and Provide Handles for Late‐Stage Derivatization
AU - Beate Nachtigall
AU - Caroline Brinkmann
AU - Jana Langosch
AU - Anke Nieß
AU - Norbert Sewald
PY - 2026
DA - 2026/08/18
JO - Chemistry (Weinheim an Der Bergstrasse, Germany)
DO - 10.1002/chem.71559
UR - https://doi.org/10.1002/chem.71559
AB - Selective targeting of integrin αVβ6 is of high relevance for molecular imaging and therapeutic applications, yet ligands combining high affinity with structural and functional versatility remain limited. A structure–activity relationship (SAR) study of the nonapeptide cyclo‐(‐Asp‐Leu‐Ala‐Phe‐d‐Pro‐NMeLys‐Phe‐Arg‐Gly‐) was performed through site‐specific substitution of phenylalanine residues by tryptophan and halogenated tryptophan derivatives, revealing a pronounced position‐dependent effect on integrin recognition. Substitution at position i+3 relative to the RGD sequence with halotryptophans is identified as an affinity hotspot, enabling picomolar binding to αVβ6. In contrast, modification at position i+6 preserves high αVβ6 affinity while providing exceptional tolerance toward structural diversification and enabling late‐stage functionalization of unprotected peptides via palladium‐catalyzed cross‐coupling reactions. This establishes i+6 modification as a versatile platform for chemoselective derivatization without compromising affinity. Halotryptophans serve both as pharmacophores and synthetic handles. Notably, an anthracenyl‐functionalized derivative combines sub‐nanomolar αVβ6 affinity with water solubility and intrinsic fluorescence, demonstrating that even bulky π‐systems can be accommodated at discrete positions without loss of potency. These integrin ligands are compatible with cellular applications and enable receptor‐specific detection by flow cytometry (FACS) as well as visualization by confocal fluorescence microscopy. This work defines a robust design for αVβ6‐targeting functional probes for molecular imaging and fluorescence‐guided tumor detection.
SN - 0947-6539
SN - 1521-3765
ER -