Department of Chemistry, Indian Institute of Science Education and Research (IISER), Dr. Homi Bhabha, Road, Pune-411008 (India), Fax: (+91) 20-2590-8186.
Chemistry. 2013 Nov 25;19(48):16256-62. doi: 10.1002/chem.201302732. Epub 2013 Oct 21.
Hybrid peptides composed of α- and β-amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ- and hybrid γ-peptides composed of γ(4) -amino acids are less studied than their β-counterparts. However, recent investigations reveal that γ(4)-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ(4)-residues with functional proteinogenic side-chains and their structural analysis in hybrid-peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-γ(4)-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-α,β-unsaturated γ-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ(4)-amino acids (γ(4)-Val, γ(4)-Leu, γ(4)-Ile, γ(4)-Thr(OtBu), γ(4)-Tyr, γ(4)-Asp(OtBu), γ(4)-Glu(OtBu), and γ-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C(γ) -C(β) bond. To study the behavior of γ(4)-residues with functional side chains in peptide sequences, two short hybrid γ-peptides P1 (Ac-Aib-γ(4)-Asn-Aib-γ(4)-Leu-Aib-γ(4)-Leu-CONH2 ) and P2 (Ac-Aib-γ(4)-Ser-Aib-γ(4)-Val-Aib-γ(4)-Val-CONH2 ) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the γ(4) -Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of γ(4)-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ(4)-residues in peptide single-crystals reveal that the γ(4)-residues in 12-helices are more ordered as compared with the 10/12- and 12/14-helices.
由α-和β-氨基酸组成的杂肽最近已成为新型肽折叠物。相比之下，由γ-和γ-氨基酸组成的γ-肽研究得较少β-对应物。然而，最近的研究表明，γ(4)-氨基酸更容易折叠成有序的螺旋结构。由于氨基酸侧链官能团在生物环境中起着至关重要的作用，本研究的目的是研究具有功能蛋白侧链的γ(4)-残基的有效合成及其在杂肽序列中的结构分析。在这里，通过多步氢解和双键还原，从 N-保护的（E）-α，β-不饱和γ-氨基酸的苄酯（COOBzl）出发，高效、对映纯合成了各种 N-和 C-端游离的γ(4)-残基。一锅催化氢化反应是报告的。八种未保护的γ(4)-氨基酸（γ(4)-Val、γ(4)-Leu、γ(4)-Ile、γ(4)-Thr（OtBu）、γ(4)-Tyr、γ(4)-Asp（OtBu）、γ(4)-Glu（OtBu）和γ-Aib）的晶体构象表明，这些氨基酸沿中心 C(γ)-C(β)键采用有利于 gauche 构象的螺旋。为了研究具有功能侧链的γ(4)-残基在肽序列中的行为，设计并合成了两个短的杂γ-肽 P1（Ac-Aib-γ(4)-Asn-Aib-γ(4)-Leu-Aib-γ(4)-Leu-CONH2）和 P2（Ac-Aib-γ(4)-Ser-Aib-γ(4)-Val-Aib-γ(4)-Val-CONH2），并在固相上进行了合成，研究了它们在单晶中的 12-螺旋构象。值得注意的是，P1 中的γ(4)-Asn 残基通过侧链酰胺基团之间的分子间氢键促进四聚体螺旋聚集。此外，P2 中γ(4)-Ser 的羟基侧链与骨架酰胺基团参与分子间氢键。此外，对 87 个γ(4)-残基在肽单晶中的分析表明，与 10/12-和 12/14-螺旋相比，12-螺旋中的γ(4)-残基更有序。
