MULTICYCLIC POLYPEPTIDE MODEL COMPOUNDS .2. SYNTHESIS AND CONFORMATIONAL PROPERTIES OF A HIGHLY ALPHA-HELICAL UNCOSAPEPTIDE CONSTRAINED BY 3 SIDE-CHAIN TO SIDE-CHAIN LACTAM BRIDGES
MULTICYCLIC POLYPEPTIDE MODEL COMPOUNDS .2. SYNTHESIS AND CONFORMATIONAL PROPERTIES OF A HIGHLY ALPHA-HELICAL UNCOSAPEPTIDE CONSTRAINED BY 3 SIDE-CHAIN TO SIDE-CHAIN LACTAM BRIDGES
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DOI：
10.1021/ja00044a003
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发表时间：
1992-08-26
影响因子：
15
通讯作者：
TAYLOR, JW
中科院分区：
文献类型：
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作者：
OSAPAY, G;TAYLOR, JW
根据我们早期报道的环（3- 7，10 - 14，17 -21）-H-[LysLeuLysGluLeuLysGlu]3-OH（1-1-1）的合成和构象性质（Osapay和Taylor，J.Am. 1990，112，6046 -6051），两种新的两亲性α-螺旋肽，环合成了（3- 7，10 - 14，17 -21）-H-[LysLeuLysGluLeuLysAsp]3-OH（2-2-2）及其线性同系物H-[LysLeuLys（Ac）GluLeuLysLeuGln]3-OH（3-3-3），以评估连接Lys（i）的多个内酰胺桥的相对螺旋稳定性质，Glu（i+4）和Lys（i）、Asp（i+4）残基对。使用Kaiser肟树脂上的固相肽合成和溶液相片段缩合的组合组装这些肽。在制备2-2-2的受保护的7-残基结构单元（7）的过程中，肽环化并伴随从肟树脂上裂解产生54%的产物。圆二色性分光光度法表明，模型肽2-2-2在pH 7.0的水性缓冲液中，在25 ℃下是高度螺旋的（[θ]222 = -23 800 deg.cm2 dmol-1）。这种桥接的螺旋结构对热和化学变性具有抗性，在90 ℃下不完全展开，并且基于[θ]222，在25 ℃下在7.30 M盐酸胍中仅50%展开。相比之下，肽1-1-1和无环肽3-3-3在水性缓冲液中均显示出非常小的螺旋特征，并且容易被盐酸胍变性。然而，在50%的三氟乙醇中或结合到疏水涂层的石英载玻片上，多环肽1-1-1和2-2-2给出了几乎相同的CD光谱，表明高度α-螺旋构象（[θ]222 =-31000 deg-cm 2 dmol-1），而线性肽3-3-3的螺旋明显较低。从这些结果中，我们得出结论：连接Lys（i），Asp（1+4）残基对侧链的多个内酰胺桥是强螺旋稳定的，而连接Lys（i），Glu（i+4）残基对侧链的多个内酰胺桥是弱螺旋稳定的。
Further to our earlier report of the synthesis and conformational properties of cyclo(3-7,10-14,17-21)-H-[LysLeuLysGluLeuLysGlu]3-OH (1-1-1) (Osapay and Taylor, J. Am. Chem. Soc. 1990,112,6046-6051), two new amphiphilic alpha-helical peptides, cyclo(3-7,10-14,17-21)-H-[LysLeuLysGluLeuLysAsp]3-OH (2-2-2) and its linear homologue H-[LysLeuLys(Ac)GluLeuLysLeuGln]3-OH (3-3-3), have been synthesized in order to assess the relative helix stabilizing properties of multiple lactam bridges linking Lys(i),Glu(i+4) and Lys(i),Asp(i+4) residue pairs. These peptides were assembled using a combination of solid-phase peptide synthesis on the Kaiser-oxime resin and solution-phase segment condensations. During the preparation of the protected 7-residue building unit (7) for 2-2-2, peptide cyclization with concomitant cleavage from the oxime resin yielded 54% product. Circular dichroism spectropolarimetry indicated that model peptide 2-2-2 was highly helical in aqueous buffer, pH 7.0, at 25-degrees-C ([theta]222 = -23 800 deg.cm2 dmol-1). This bridged helical structure was resistant to thermal and chemical denaturation, being incompletely unfolded at 90-degrees-C and, based on [theta]222, only 50% unfolded in 7.30 M guanidinium hydrochloride at 25-degrees-C. In contrast, peptide 1-1-1 and the acyclic peptide 3-3-3 both displayed very little helical character in the aqueous buffer and were readily denaturated by guanidinium hydrochloride. However, in 50% trifluoroethanol or bound to hydrophobic coated quartz slides, the multicyclic peptides 1-1-1 and 2-2-2 gave almost identical CD spectra indicative of a highly a-helical conformation ([theta]222 = - 31 000 deg-cm2 dmol-1), whereas the linear peptide 3-3-3 was significantly less helical. From these results, we conclude that multiple lactam bridges linking the side chains of Lys(i),Asp(1+4) residue pairs are strongly helix stabilizing, and those linking Lys(i),Glu(i+4) residue pairs are weakly helix stabilizing.