Solid-phase strategies for the assembly of template-based protein mimetics

The template concept for overcoming the protein folding problem in protein de novo design has recently been extended for mimicking essential structura l and functional features of proteins. Due to progress in synthetic methodo logies, template-assembled constructs now become accessible for efficient s olid-phase strategies, as exemplified for three prototype protein mimetics. As a key step, regioselectively addressable functional template molecules are prepared by convergent methods and immobilized on solid support (2b in Figure 1). Up to four orthogonal amino protecting groups, i.e., Fmoc, Alloc , Dde, and pNZ, allow for the step-by-step synthesis of protein surface mim etic 3, template-assembled synthetic protein (TASP) 4, and the convergent s ynthesis of receptor mimetic 5 in good overall yield. The elaborated protoc ols extend today's potential of solid-phase peptide synthesis for the const ruction of molecules of high structural complexity and open the way to temp late-based protein mimetics by combinatorial techniques.