Universal Peptidomimetics

• Published in: Journal of the American Chemical Society Vol. 133; no. 3; pp. 462 - 477
• Main Authors: Ko, Eunhwa, Liu, Jing, Perez, Lisa M, Lu, Genliang, Schaefer, Amber, Burgess, Kevin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.01.2011; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Kinetics; Models, Molecular; Peptidomimetics; Physical Sciences; Protein Structure, Secondary; Quantum Theory; Science & Technology; Thermodynamics; PEPTIDE LIGANDS; DIPEPTIDE ISOSTERES; MOLECULAR-DYNAMICS; NONPEPTIDE PEPTIDOMIMETICS; CYCLIC HEXAPEPTIDES; BETA-D-GLUCOSE; PROTEIN-PROTEIN INTERACTIONS; CONFORMATIONAL-ANALYSIS; HYDROGEN-BOND SURROGATE; SHORT ALPHA-HELICES
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja1071916

This paper concerns peptidomimetic scaffolds that can present side chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analogue local pairs of amino acids (including noncontiguous ones) in any secondary structure; i.e., they are universal peptidomimetics. To illustrate this concept, we designed a set of four peptidomimetic scaffolds. Libraries based on them were made bearing side chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together, peptidomimetics based on these four scaffolds can adopt conformations that resemble almost any combination of local amino acid side chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high-throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) are outlined.