Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β-hairpin-like scaffold, MTI-101.
Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β-hairpin-like scaffold, MTI-101.
复制标题
通过在环状β-发蛋白样支架MTI-101中显示Hyd1疏水核的生物活性改善。
DOI：
10.1002/pep2.24199
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发表时间：
2021-05
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影响因子：
--
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中科院分区：
文献类型：
--
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HYD 1是一种全D-氨基酸线性10聚体肽，通过一珠一化合物筛选发现。HYD 1具有5个疏水氨基酸，两侧为极性氨基酸。丙氨酸扫描研究表明，交替的疏水性氨基酸残基和N-和C-末端赖氨酸侧链是线性10-mer类似物生物活性的贡献者。这一观察结果使我们假设，在环状β-发夹样支架中展示HYD 1的疏水五肽序列可以导致更好的生物利用度和生物活性。使用两亲性五肽序列形成反平行链，并且这些链通过选择以促进β转角的二肽样序列连接。早期的环状类似物更有活性，但在其他方面模仿线性HYD 1肽的生物活性。使用标准Fmoc固相合成法合成环状肽模拟物以形成线性肽，然后进行溶液相或树脂上环化。进行SAR研究的目的是增加这些候选药物在体外杀死多发性骨髓瘤细胞的效力。1、5和10的溶液结构使用NMR光谱进行了解析。这些肽的1H NMR和2D TOCSY研究显示低场Hα质子化学位移和2D NOE光谱分析与β-发夹样结构一致。
HYD1 is an all D‐amino acid linear 10‐mer peptide that was discovered by one‐bead‐one‐compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N‐ and C‐terminal lysine side chains were contributors to the biological activity of the linear 10‐mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic beta‐hairpin‐like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide‐like sequences selected to promote β‐turns. Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on‐resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells in vitro. The solution structures of 1, 5, and 10 were elucidated using NMR spectroscopy. 1H NMR and 2D TOCSY studies of these peptides revealed a downfield Hα proton chemical shift and 2D NOE spectral analysis consistent with a β‐hairpin‐like structure.
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影响因子：
5.7
作者：
Gebhard AW;Jain P;Nair RR;Emmons MF;Argilagos RF;Koomen JM;McLaughlin ML;Hazlehurst LA
通讯作者：
Hazlehurst LA
影响因子：
2.7
作者：
Rabinowitz, M;Seneci, P;Terstappen, G
通讯作者：
Terstappen, G
影响因子：
5.6
作者：
WISHART, DS;SYKES, BD;RICHARDS, FM
通讯作者：
RICHARDS, FM
影响因子：
5.7
作者：
Nair RR;Emmons MF;Cress AE;Argilagos RF;Lam K;Kerr WT;Wang HG;Dalton WS;Hazlehurst LA
通讯作者：
Hazlehurst LA
影响因子：
20.3
作者：
Damiano, JS;Cress, AE;Dalton, WS
通讯作者：
Dalton, WS