Synthesis and Conformational Analysis of Linear and Cyclic Peptides Containing Sugar Amino Acids

Abstract

Sugar amino acids (SAAs) were designed and synthesized as new non-peptide peptidomimetics utilizing carbohydrates as peptide building blocks. They represent sugar-like ring structures that carry an amino and a carboxylic functional group and have a specific conformational influence on the backbone of peptides due to their distinct substitution patterns in rigid pyranose sugar rings. Five different SAAs (SAA1R, SAA1β, SAA2, SAA3, and SAA4) have been synthesized that show the ability to constrain linear backbone conformations or distinct turn structures. Linear and cyclic peptides involving SAAs have been prepared in solution as well as by solid phase synthesis. SAA1R and SAA2 were incorporated into two linear Leu-enkephalin analogs, replacing the natural Gly-Gly dipeptide. NMR studies provide evidence for the conformation-inducing effect of the carbohydrate moiety. SAA2 and SAA3 have been placed in cyclic hexapeptide analogs of somatostatin; SAA4 was incorporated in a model peptide. The conformation of the cyclic peptides cyclo(-SAA2-Phe-D-Trp-Lys-Thr-), cyclo(-SAA3-Phe-D-Trp-Lys(Boc)-Thr(tBu)-), and cyclo(-SAA4-Ala-D-Pro-Ala-Ala-) have been analyzed by various NMR techniques in combination with distance geometry calculations and subsequent molecular dynamic simulations. The determined solution conformations were compared to representative idealized peptide backbones. SAA2 and SAA3 induce a β-turn structure while SAA4 mimics a γ-turn. Both enkephalin analogs were not active in the guinea pig ileum assay. The somatostatin analog containing SAA2 has an inhibition constant (IC 50 ) of 0.15 µM for the inhibition of the release of growth hormone.

Synthesis and Use of Tetrahydrofuran- and Tetrahydropyran-Amino Acids

“…Kessler et al synthesized the cis THPenkephalin analog 73 with the opposite absolute configuration at C-2 and C-6 of the THP ring. For this compound no significant bioactivity was reported [4]. …”

“…It was found, that 1 acts as a linear dipeptide isoster, 2 and 3 are β-turn mimetics and 4 induces a γ-turn. The synthesis of 4 is shown in scheme 1 [4]. D-Glucoseamine was converted into the benzyl-protected compound 5.…”

Carbohydrates in peptide and protein design

“…54,55 Such sequences prepared by Chakraborty et al 56,57 have shown analgesic activity similar to that of Leuenkephalin methyl ester. Similarly, Drouillat et al 58 has used SAAs to form glycosylated enkephalins via amide bond linkages to the C-terminal.…”

Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

“…The most interesting feature displayed by d-amino acids is their structural analogy with dipeptides, and many d-amino acids as peptidomimetics have been constructed to mimic dipeptide sequences with added structural constraints . Relevant examples of d-amino acids include linear (Wipf et al, 1998;Gardner et al, 1999;Shankaramma et al, 1999;Casimir et al, 2000), cyclic (Poitout et al, 1995;Graf von Roedern et al, 1996;Suhara et al, 1996;Wattersom et al, 2003;Durrat et al, 2004), bicyclic (Hanessian et al, 1997;Van Well et al, 2003), and spiro (Genin and Johnson, 1992;Khalil et al, 1999;Alonso et al, 2001) compounds, and different templates have been applied for the generation of such amino acids. Moreover, since the b-turn is a common structural feature of proteins associated with the dipeptide unit, much research about d-amino acids has been concentrated on the creation of reverse turn mimetics, where the central amide bond is replaced by a rigid moiety (Kim and Germanas, 1997a, b;Belvisi et al, 1999;Estiarte et al, 2000;Trabocchi et al, 2002).…”