D‐Isomeric replacements within the 6–9 core sequence of ac‐[Nle4]‐α‐MSH4–11‐NH2: A topological model for the solution conformation of α‐melanotropin
D‐Isomeric replacements within the 6–9 core sequence of ac‐[Nle4]‐α‐MSH4–11‐NH2: A topological model for the solution conformation of α‐melanotropin
复制标题
ac-[Nle4]-α-MSH4-11-NH2 的 6-9 核心序列内的 D-异构体替换：α-促黑激素溶液构象的拓扑模型
DOI：
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复制
发表时间：
1986
期刊：
影响因子：
--
通讯作者：
V. Hruby
中科院分区：
文献类型：
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作者：
E. Sugg;W. L. Cody;Z. Abdel‐Malek;M. Hadley;V. Hruby
制备Ac-[Nle 4]-α-MSH 4 -11-NH 2和Ac-[Nle 4，D-Phe 7]-α-MSH 4 -11-NH 2的类似物，其中在His 6、Arg 8和Trp 9残基处进行D-异构体置换。还通过在两个亲本片段类似物中用L-亮氨酸替换来评估在位置9处对吲哚部分的需求。在体外促黑素试验中，任一系列中位置6和8处的D-异构体置换对青蛙（蛙）和蜥蜴皮（Anolis carolinensis）的生物效价有害。然而，在蜥蜴皮肤生物测定中，Ac-[Nle 4，D-Trp 9]-α-MSH 4 -11-NH 2和Ac-[Nle 4，D-Phe 7，D-Trp 9]-α-MSH 4 - 11-NH 2的效力相等，分别比Ac-[Nle 4]-α-MSH 4 -11-NH 2的效力高10倍，在青蛙皮肤生物测定中，效力高30倍和1900倍。在青蛙皮肤生物测定中，Ac-[Nle 4，D-Phe 7，D-Trp 9]-α-MSH 4 -11-NH 2的效力是α-MSH的3倍。水溶液中的质子核磁共振研究表明，这些线性类似物的骨架构象有明显的保留。由于核心芳香族氨基酸残基的通过空间各向异性影响导致的化学位移变化允许评价侧链拓扑结构。观察到的拓扑结构与非氢键β-样结构（L-氨基酸的ε = −139°，ε = +135°; D-氨基酸的ε = +139°，ε = −135°）作为主要溶液构象一致。生物学和构象数据表明，高促黑素效力需要His 6、Phe 7和Arg 8侧链的紧密空间排列。
Analogs of Ac‐[Nle4]‐α‐MSH4–11‐NH2 and Ac‐[Nle4, D‐Phe7]‐α‐MSH4–11‐NH2 were prepared with D‐isomeric replacements at the His6, Arg8, and Trp9 residues. The requirement for an indole moiety at position 9 also was evaluated by replacement with L‐leucine in both parent fragment analogs. D‐isomeric replacements at positions 6 and 8 in either series were detrimental to biological potency in frog (Rana pipiens) and lizard skin (Anolis carolinensis) in vitro melanotropic assays. However, Ac‐[Nle4, D‐Trp9]‐α‐MSH4–11‐NH2 and Ac‐[Nle4, D‐Phe7, D‐Trp9]‐α‐MSH4–11‐NH2 were equipotent and 10 × more potent than Ac‐[Nle4]‐α‐MSH4–11‐NH2, respectively, in the lizard skin bioassay, and 30 and 1900 times more potent in the frog skin bioassay. Ac‐[Nle4, D‐Phe7, D‐Trp9]‐α‐MSH4–11‐NH2 was 3 × more potent than α‐MSH in the frog skin bioassay. Proton nmr studies in aqueous solution revealed a marked preservation of the backbone conformation of these linear analogs. Chemical‐shift variations due to the through‐space anisotropic influence of the core aromatic amino acid residues permitted evaluation of side‐chain topology. The observed topology was consistent with nonhydrogen‐bonded β‐like structure (ϕ = −139°, ψ = +135° for L‐amino acids; ϕ = +139°, ψ = −135° for D‐amino acids) as the predominant solution conformation. The biological and conformational data suggest that high melanotropic potency requires a close spatial arrangement of the His6, Phe7, and Arg8 side chains.
DOI：
10.1073/pnas.77.10.5754
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
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作者：
SAWYER, TK;SANFILIPPO, PJ;HADLEY, ME
通讯作者：
HADLEY, ME
促黑激素结构特征的分化对于生物效力和体外延长活性很重要。
DOI：
10.1111/j.1399-3011.1983.tb02097.x
发表时间：
1983
期刊：
International journal of peptide and protein research
影响因子：
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作者：
Wilkes,BC;Sawyer,TK;Hruby,VJ;Hadley,ME
通讯作者：
Hadley,ME
影响因子：
56.9
作者：
HADLEY, ME;ANDERSON, B;HRUBY, VJ
通讯作者：
HRUBY, VJ