Peptidomimetics for bridging structure and function: Pseudo-pralines (ψPro) in peptide synthesis, molecular recognition, and drug design

Abstract

The central issue of bioorganic chemistry is to unravel the structural and functional complexity of living systems by designing synthetic models that mimic essential features of biomolecules. In view of the expected exponential growth of knowledge within the next decade about structure-activity relationships in bioactive compounds as well as about mechanisms of molecular recognition in cellular communication, conversion of the design of therapeutically relevant molecules currently provides one of the most fascinating challenges for synthetic organic chemistry. Independent of evolutionary restrictions in creating the molecules of life, the chemist may even go a step further in extending Nature's pool of biomolecules for studying biochemical processes. One way of doing this is illustrated in the present article. Taking proline (Pro) as a unique building block in peptides and proteins, we have explored its particular role in a variety of biological processes by tuning its intrinsic structural and functional properties using readily accessible proline mimetics ('pseudopralines', ψPro). In enhancing and extending well-known Pro effects, i.e. cis-trans amide bond isomerization, conformational restriction or specific receptor interaction, ψPro derivatives are useful as synthetic tools in molecular recognition studies and for modulating the physicochemical, pharmacokinetic and biological properties of peptide and protein ligands. Selected examples from our ongoing research program in peptidomimetic chemistry demonstrate that synthetic tools can substantially contribute to our understanding of fundamental principles underlying biological processes and serve as a first step in accessing molecules of therapeutic relevance.