Peptidomimetics for bridging structure and function: Pseudo-prolines (Psi Pro) in peptide synthesis, molecular recognition, and drug design

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 exponenti al growth of knowledge within the next decade about structure-activity rela tionships in bioactive compounds as well as about mechanisms of molecular r ecognition in cellular communication, conversion of the design of therapeut ically relevant molecules currently provides one of the most fascinating ch allenges for synthetic organic chemistry. Independent of evolutionary restr ictions in creating the molecules of life, the chemist may even go a step f urther in extending Nature's pool of biomolecules for studying biochemical processes. One way of doing this is illustrated in the present article. Tak ing proline (Pro) as a unique building block in peptides and proteins, we h ave explored its particular role in a variety of biological processes by tu ning its intrinsic structural and functional properties using readily acces sible proline mimetics ('pseudo-prolines', Psi Pro). In enhancing and exten ding well-known Pro effects, i.e. cis-trans amide bond isomerization, confo rmational restriction or specific receptor interaction, Psi Pro derivatives are useful as synthetic tools in molecular recognition studies and for mod ulating the physicochemical, pharmacokinetic and biological properties of p eptide and protein ligands. Selected examples from our ongoing research pro gram in peptidomimetic chemistry demonstrate that synthetic tools can subst antially contribute to our understanding of fundamental principles underlyi ng biological processes and serve as a first step in accessing molecules of therapeutic relevance.