Catalytic peptide dendrimers.

Abstract

Listen

Translate article

Enzyme catalysis is made possible by the folding of linear peptide chains into well-defined three-dimensional structures. The aim of de novo enzyme design is to create selective catalysts through the catalytically productive combination of amino acids.[1] A variety of a-helical peptides have been designed that are catalytically active.[2] Thus, the spatial proximity of amino acid side chains placed one turn apart in an a helix were shown to induce catalysis. Protected b-turn peptides have been found to be selective catalysts in organic solvents.[3] Such approaches have required the linear peptides to form a properly folded structure for catalysis to be observed. Alternatively one can design three-dimensional structures by chemical synthesis using a dendrimeric architecture, which enforces a globular shape by steric crowding and therefore obviates the folding requirement and greatly simplifies design.[4] Whereas catalytic dendrimers based on ether linkages and incorporating catalytically active subunits such as metal complexes and cofactors are known,[5] peptide dendrimers have to date only been reported as antigendisplay units (multiple antigenic peptides)[6] or in structural studies.[7] Herein we report the preparation of the first catalytic peptide dendrimers. The peptide dendrimers exhibit enzymelike kinetic properties, including selective substrate binding and rate acceleration in aqueous media. We prepared dendrimeric peptides with the sequence ((CapCONH-A)2BA)2B-Cys-A-NH2 (Scheme 1). The symmetrical, achiral diamino acid (1,3-diaminoisopropyloxy)acetic acid was chosen as the branching unit B, which provides the dendrimeric architecture. The sequences were terminated by acylation with the 3-dimethylaminoisophthaloyl group (= Cap, introduced as the mono-tert-butyl ester), which provided a spectroscopic signature and allowed the homogeneous solubility of the dendrimers under both the acidic conditions of HPLC purification and the neutral conditions of aqueous buffers. Permutations of the catalytic triad of the amino acids histidine (His), aspartate (Asp), and serine (Ser) were chosen as the variable positions A1, A2, and A3 to generate a family of esterolytic peptide dendrimers. The solid-phase peptide synthesis was carried out on a Rink amide resin with Fmoc-