Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification
Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification
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通过疏水残基定向结构修饰开发有效的肌肉生长抑制素抑制肽
DOI：
10.1021/acsmedchemlett.7b00168
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发表时间：
2017
影响因子：
4.2
通讯作者：
Hayashi Yoshio
中科院分区：
文献类型：
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作者：
Takayama Kentaro;Rentier Cedric;Asari Tomo;Nakamura Akari;Saga Yusuke;Shimada Takahiro;Nirasawa Kei;Sasaki Eri;Muguruma Kyohei;Taguchi Akihiro;Taniguchi Atsuhiko;Negishi Yoichi;Hayashi Yoshio
肌生长抑制素是骨骼肌生长的负调节因子，是治疗肌肉萎缩性疾病的一个有前途的靶点。最近，我们发现了一个最小的肌肉生长抑制素的前结构域的位置21-43的衍生的肌肉生长抑制素的前体1（WRQNTRYSRIEAIKIQILSKLRL-酰胺）。我们先前通过基于1的构效关系（SAR）研究确定了有效抑制所需的关键残基（N-末端Trp 21、啮齿动物特异性Tyr 27和所有脂肪族氨基酸），并表征了在21位具有2-萘氧基乙酰基的3倍更有效的抑制剂2。在此，我们进行了基于1的SAR研究，重点是所有的脂肪族残基和Ala 32，发现在位置32和38的色氨酸和异亮氨酸的取代，分别增强了抑制活性。将这些发现与2相结合，一种新的肽3d显示出0.32 μM的IC 50值，其效力是1的11倍。肽3d有可能成为一种很有前途的药物，从而开发出更好的肽模拟物。
Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor1(WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21–43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp21, rodent-specific Tyr27, and all aliphatic amino acids) required for effective inhibition through structure–activity relationship (SAR) studies based on1and characterized a 3-fold more potent inhibitor2bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed1-based SAR studies focused on all aliphatic residues and Ala32, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with2, a novel peptide3ddisplayed an IC50value of 0.32 μM, which is 11 times more potent than1. The peptide3dwould have the potential to be a promising drug lead to develop better peptidomimetics.