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 structural and functional features of proteins. Due to progress in synthetic methodologies, template-assembled constructs now become accessible for efficient solid-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 mimetic 3, template-assembled synthetic protein (TASP) 4, and the convergent synthesis of receptor mimetic 5 in good overall yield. The elaborated protocols extend today's potential of solid-phase peptide synthesis for the construction of molecules of high structural complexity and open the way to template-based protein mimetics by combinatorial techniques.