Beta-peptidic peptidomimetics.
For more than a decade now, a search for answers to the following two questions has taken us on a new and exciting journey into the world of beta- and gamma-peptides: What happens if the oxygen atoms in a 3i-helix of a polymeric chain composed of (R)-3-hydroxybutanoic acid are replaced by NH units? What happens if one or two CH2 groups are introduced into each amino acid building block in the chain of a peptide or protein, thereby providing homologues of the proteinogenic alpha-amino acids? Our journey has repeatedly thrown up surprises, continually expanding the potential of these classes of compound and deepening our understanding of the structures, properties, and multifaceted functions of the natural "models" to which they are related. Beta-peptides differ from their natural counterparts, the alpha-peptides, by having CH2 groups inserted into every amino acid residue, either between the C=O groups and the alpha-carbon atoms (beta(3)) or between the alpha-carbon and nitrogen atoms (beta(2)). The synthesis of these homologated proteinogenic amino acids and their assembly into beta-peptides can be performed using known methods. Despite the increased number of possible conformers, the beta-peptides form secondary structures (helices, turns, sheets) even when the chain lengths are as short as four residues. Furthermore, they are stable toward degrading and metabolizing enzymes in living organisms. Linear, helical, and hairpin-type structures of beta-peptides can now be designed in such a way that they resemble the characteristic and activity-related structural features ("epitopes") of corresponding natural peptides or protein sections. This Account presents examples of beta-peptidic compounds binding, as agonists or antagonists (inhibitors), to (i) major histocompatibility complex (MHC) proteins (immune response), (ii) the lipid-transport protein SR-B1 (cholesterol uptake from the small intestine), (iii) the core (1-60) of interleukin-8 (inflammation), (iv) the oncoprotein RDM2, (v) the HIVgp41 fusion protein, (vi) G-protein-coupled somatostatin hsst receptors, (vii) the TNF immune response receptor CD40 (apoptosis), and (viii) DNA. Short-chain beta-peptides may be orally bioavailable and excreted from the body of mammals; long-chain beta-peptides may require intravenous administration but will have longer half-lives of clearance. It has been said that an interesting field of research distinguishes itself in that the results always throw up new questions; in this sense, the structural and biological investigation of beta-peptides has been a gold mine. We expect that these peptidic peptidomimetics will play an increasing role in biomedical research and drug development in the near future.
Seebach
Dieter
D
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland. seebach@org.chem.ethz.ch
Gardiner
James
J
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry*; D004247:DNA / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats
D000596:Amino Acids; D010455:Peptides; D011506:Proteins; D012313:RNA; D004247:DNA