In proteins, the aromatic side chains of the amino acids phenylalanine, tyrosine, and tryptophane are frequently involved in π interactions, which are often crucial for protein structure, stability, as well as protein-ligand binding and interaction with other macromolecules in general. In contrast to Phe and Tyr, Trp also bears an indole N-H moiety that can donate a hydrogen bond, and as a result, Trp can also facilitate the solvation of folded proteins.

A powerful tool to study, modify, and optimize protein-ligand or protein-protein interactions is the screening with differently substituted non-canonical amino acid derivatives. For example, the introduction of a strongly electronegative fluorine atom on the aromatic ring of the Trp side chain decreases the electron density of the aromatic system and thereby alters the binding interactions.

Thus, the use of amino acid analogs may help to extend your drug's half-life, increase protease resistance, and prevent oxidation. Besides, slight structural changes may allow to tune the rigidity and permeability of drugs to penetrate cells or to cross the blood-brain barrier. In addition, modified Tryptophans have proven their usefulness in studies of protein structure and of protein-protein association.

For drug discovery and structure-activity optimization, Iris Biotech is offering four different sets of Tryptophan-related non-canonical amino acids. Each set includes 50 mg of each of the listed amino acids with >95% purity. All derivatives can also be provided with Fmoc-protection, also as screening sets.

Set 1: Cyano-tryptophans with the substituent at positions 4, 5, 6 and 7.

Set 2: N-Methyl-fluoro-tryptophans with the substituent at positions 4, 5, 6 and 7.

Set 3: Aza-tryptophans with the substituent at positions 4, 5, 6 and 7, and β-indazol-1-yl-alanine.

Set 4: Bromo-4-hydroxy-naphth-1-yl-alanins with the substituent at positions 3, 5, 6 and 7.

Larger quantities of each of the amino acids are available on demand. Other non-canonical Tryptophan and Tyrosine analogs can be provided on request.

References:

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Scalable continuous evolution for the generation of diverse enzyme variants encompassing promiscuous activities; G. Rix, E. J. Watkins-Dulaney, P. J. Almhjell, C. E. Boville, F. H. Arnold, C. C. Liu; Nature Communications 2020; 11: 5644. https://doi.org/10.1038/s41467-020-19539-6

Tryptophan-based fluorophores for studying protein conformational changes; P. Talukder, S. Chen, C. T. Liu, E. A. Baldwin, S. J. Benkovic, S. M. Hecht; Bioorganic & Medicinal Chemistry 2014; 22: 5924-5934. https://doi.org/10.1016/j.bmc.2014.09.015

Cyanotryptophans as Novel Fluorescent Probes for Studying Protein Conformational Changes and DNA–Protein Interaction; P. Talukder, S. Chen, B. Roy, P. Yakovchuk, M. M. Spiering, M. P. Alam, M. M. Madathil, C. Bhattacharya, S. J. Benkovic, S. M. Hecht; Biochemistry 2015; 54: 7457-7469. https://doi.org/10.1021/acs.biochem.5b01085

Tryptophan Synthase: Biocatalyst Extraordinaire; E. Watkins-Dulaney, S. Straathof, F. Arnold; Chembiochem: a European journal of chemical biology 2021; 22: 5-16. https://doi.org/10.1002/cbic.202000379

The Role of Tryptophan in p Interactions in Proteins: An Experimental Approach; J. Shao, B. P. Kuiper, A.-M. W. H. Thunnissen, R. H. Cool, L. Zhou, C. Huang, B. W. Dijkstra, J. Broos; J. Am. Chem. Soc. 2022; 144(30): 13815-13822. https://doi.org/10.1021/jacs.2c04986