Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 44

Fig. 13 Perturbation of protein-ligand interactions by modulating the cation-pi interaction. (a)
Peptides bearing trimethyllysine -N(Me 3 ) + and neutral -C(Me 3 ) + side chains, as well as the parent
peptide with an unmodified lysine (-NH 3 + ) side chain, and their affinities for the aromatic cage
protein HP1. The HP1 binding pocket containing bound trimethyllysine is shown at left (1KNE).
(b) Two inhibitors of the enzyme Factor Xa that show 100-fold increased potency for the -N
(Me 3 ) + type inhibitor. (c) Electron-deficient Trp analogs are introduced into nicotinic acetylcho-
line receptor (nAChR) at position 149 by mutagenesis. The resulting receptors show reduced

activation by the agonist epibatidine with increasing fluorination, demonstrating the importance of
the Trp149-epibatidine cation-pi interaction

a

by the dramatic weakening of protein-ligand interactions for the proteins with more
highly fluorinated, and therefore more electron-poor aromatics.
Trp is the most electron-rich of the aromatic amino acids, and as such is the
aromatic residue most frequently identified as participating in strong cation-pi
interactions in nature [ 63 ]. In recent work, our group has been creating new aromatic
cage mimics that involve the incorporation of Trp into receptor frameworks of
different types. One variation on this theme involves the construction of small
Trp-rich peptides, with augmentation of their aromatic character by incorporation
of N -benzyltryptophan as a building block [ 64 ]. This artificial amino acid presents
both the electron-rich indole and an appended benzyl substituent to cationic binding
partners. The peptide-derived receptor Trp(Bn)-Trp(Bn) (33) shows the ability to
bind to quaternary ammonium ions in water, with selectivity over unmethylated
primary quaternary ammonium ions in this highly competitive medium. More
telling, the construction and comparison of receptors based on Trp-Trp peptides
(33-35) bearing zero, one, and two appended benzyl substituents showed an increas-
ing ability to bind to acetylcholine in water with increasing benzylation (Fig. 14 ).
In another approach, we have created a variety of hosts based on indole carbox-
ylic acids, including receptor 37 made from three copies of the de-aminated Trp
building block indole-3-propionic acid (36, Fig. 15 )[ 65 ]. Despite its extreme