The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.
New classes of alpha/gamma- and beta/gamma-hybrid peptides have been synthesized with novel 12/10- and 11/13-mixed helical patterns, respectively. The alpha/gamma-peptides were derived from the dipeptide repeats with alternating arrays of l-Ala and gamma-Caa((l)) (C-linked carbo-gamma-amino acid from d-mannose), which generated a new 12/10-mixed helix, for the first time, without a beta-amino acid. The beta/gamma-peptides made from an alternating arrangement of beta-Caa((x)) (C-linked carbo-beta-amino acid) and gamma-Caa((x)) (C-linked carbo-gamma-amino acid from d-xylose), on the other hand, resulted in an unprecedented 11/13-helix. The secondary structures in these peptides have been ascertained from detailed NMR studies, and CD spectroscopy and molecular dynamics investigations provided additional support for the structures derived.
Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic (5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized. The synthesis followed a novel reaction path in which an intramolecular 5-exo S(N)2 opening of the hexose-derived terminal aziridine ring in 2 by the gamma-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary delta-hydroxyl group to carboxyl function, leading to the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11. Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR techniques in combination with constrained molecular dynamics (MD) simulations revealed that two of these analogues, 8a and 10a, have folded conformations composed of an unusual nine-membered pseudo beta-turn-like structure with a strong intramolecular H-bond between LeuNH --> sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proximity, a prerequisite for biological activities of opioid peptides. The analgesic activities of 8a,b determined by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The syn disposition of the beta-hydroxycarboxyl motif on the sugar rings appears to be the driving force to nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-anhydro-D-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical peptide strands led to the formation of a C2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH --> sugar-OH, the same as in 8 and 10.
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