Template Assembled Synthetic Proteins (TASP) as Functional Mimetics of Proteins

Abstract

The use of peptidomimetics and topological templates has become an important tool in protein design and mimicry." -4 1 By introducing these elements in the design process, the synthetic chemist aims to unravel the complex interplay between protein structure and function. In order to avoid the well-known protein folding problem, we have introduced the concept of template assembled synthetic proteins (TASP); here, templates serve as built-in devices for directing the intramolecular assembly of covalently attached peptide blocks into characteristic folding t o p~l o g i e s .~~ So far, problems with the synthesis have prevented the development of the full potential of this app r~a c h . '~] According to the TASP approach, the functional part of a protein, for example the antigen binding site of an antibody or the ligand binding site of a receptor, is detached from the rest of the molecule and assembled on a topological template, which mimics the loop supporting structural framework of the native protein (Fig. 1). Here, we elaborate the methodologies for the synthesis of this novel generation of functional TASP compounds.The approach comprises two key elements: 1) peptide sequences (loops) containing C-and N-terminal functional-

Molecular modeling and design of regioselectively addressable functionalized templates with rigidified three-dimensional structures

“…A number of most encouraging applications of this concept have been reported recently. [11][12][13][14][15] As template molecules, constrained cyclic peptides or stabilized secondary structure elements such as helices, sheets, loops, or turns proved to be versatile structural motifs for disposing selectively addressable groups. Alternative motifs such as cyclodextrins, glycosidic moieties, or polycyclic systems might also be feasible templates for specific applications.…”

A Fully Solid-Phase Synthesis of Biotinylated Glycoclusters

“…It requires a careful choice of solid support as well as suitable orthogonal protecting groups for amino acids to ensure the controlled assembly and the regioselective functionalization of the peptide. Our cyclic scaffold has been designed on the basis of the Template Assembled Synthetic Protein (TASP) model which was previously described for protein de novo design [20]. It exhibits two independent addressable domains displaying lysine residues as anchoring sites.…”

Functional Reconstruction of Structurally Complex Epitopes using CLIPS™ Technology

“…1B) linear peptides generally fail, because they do not adopt the correct secondary and tertiairy structure. For that purpose, more elaborate tools are needed to position correctly the important functionalities in space, which is an absolute prerequisite for activity [12][13][14].…”