Bicyclic Organo‐Peptides as Selective Carbohydrate Receptors: Design, Solid‐phase Synthesis, and on‐bead Binding Capability

Abstract

Selective recognition of monosaccharides in polar media by conformationally restricted bicyclic peptides containing an aromatic surface to facilitate the initial interaction has been examined. Molecular modeling assisted design of these peptidic receptors has been employed to optimize guest fitting in the peptide cavity. Different solid-phase synthetic approaches to the target structures are discussed in order to develop a flexible methodology suitable for a combinatorial approach. A series of putative receptors, differing in the aromatic spacer as well as the peptide ring size, has been synthesized and characterized by HPLC and HR-MS. They have been subjected to FRET-based screening for binding to mono and disaccharides. This indicates that binding properties are strongly dependent on the size and rigidity of the receptors, detecting b-glucoside selectivity in the case of a naphthyl-bridged cyclic dodecapeptide. In addition, an ES-MS/MS-based method that allows structural elucidation of single bead samples with no need of encoding techniques has been devised, which will be useful for structure elucidation in libraries of cyclic peptides.

Cysteine‐linked aromatic nitriles as UV resonance Raman probes of protein structure

“…Selective 4‐methoxytrityl ( para‐Monomethoxytrityl ) deprotection on cysteine (structure 7 – Scheme ) was achieved by 1% trifluoroacetic acid/triisopropylsilane/dichloromethane treatment, and the subsequent alkylation was smoothly accomplished via identical conditions to yield the desired peptides 8 and 9 (Scheme ). Polyethylene glycol‐based resin was used because of its convenient swelling in aqueous buffer, but polyethylene glycol‐based resins are not strictly required for probe incorporation …”

Specific Recognition of Disaccharides in Water by an Artificial Bicyclic Carbohydrate Receptor

“…(4) Receptor size was designed to facilitate a relatively tight fit to the glucose unit; the cyclic dodecapeptide model was derived through modelling. [16] In this arrangement, the entropic effect of releasing the organized water shell from the naphthalene bridge combined with the establishment of the CH-π interactions between the α face of the carbohydrate and the aromatic surface of the naphthalene serve as driving forces for the binding event between the carbohydrate and the receptor cavity. This allows a carbohydrate-specific H-bonding network of the hydroxy groups with the amide bonds of the peptide to be established.…”

Synthesis of Bicyclic Peptides

“…After coupling the last two amino acids and acetylation of the amino terminus, the peptide amide was deprotected and released from resin with HF. About 60 % of the peptide material had Another rather extensively used approach to obtain sidechain bridged bicyclic peptides is constraint of the structure by one side-chain lactam and one disulfide bridge (8). These may be formed independently without additional demands for the protecting group strategy.…”

“…Alternatively, a disulfide bond between two Cys residues (4) can be used to create the bicyclic structure, or two head-to-tail cyclized peptides may be linked by an amide (5) or disulfide (6) bond. Second, two pairs of side-chain functionalities may be pair wise connected with amide or disulfide bonds (7)(8)(9). Third, two side-chain cyclized monocyclic peptides can be connected by a disulfide bridge (10) or the two peptides, at least one of which is a cyclized one, are tethered to each other via two intermolecular disulfide bridges (11).…”

“…The spatially defined rigid structure [2] makes bicyclic peptides even more appropriate for applications that depend on efficient host-guest recognition. Accordingly, they have been synthesized and tested as specific ion binders [3], anticancer agents [4], protease inhibitors [5], antibiotics [6], receptor antagonists [7] and artificial receptors [8]. In addition, they serve as model compounds with which the biological role and interaction mechanisms of naturally-occuring bicyclic peptides and various structural motives of proteins may be elucidated [9].…”