Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.
Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.
复制标题
DOI：
10.1038/s41467-023-36978-z
复制
发表时间：
2023-03-17
影响因子：
16.6
通讯作者：
Sando, Shinsuke
中科院分区：
文献类型：
--
作者：
Hosono, Yuki;Uchida, Satoshi;Shinkai, Moe;Townsend, Chad E.;Kelly, Colin N.;Naylor, Matthew R.;Lee, Hsiau-Wei;Kanamitsu, Kayoko;Ishii, Mayumi;Ueki, Ryosuke;Ueda, Takumi;Takeuchi, Koh;Sugita, Masatake;Akiyama, Yutaka;Lokey, Scott R.;Morimoto, Jumpei;Sando, Shinsuke
具有高膜渗透性的天然存在的肽通常在其主链上具有酯键。然而，尚未直接评估酰胺-酯取代对肽的膜渗透性的影响。在这里，我们报告的影响，酰胺到酯取代的膜渗透性和构象合奏的环肽相关的膜渗透。酰胺-酯取代显示出改善二肽和模型环六肽的膜渗透性。基于NMR的构象分析和增强的采样分子动力学模拟表明，膜渗透后的环状六肽的构象转变是不同的影响由酰胺-酯取代和酰胺N-甲基化。其他环状六肽，环状八肽，和环状九肽的膜渗透性的酰胺酯取代的效果也进行了研究，以检查取代的范围。根据我们的研究结果，适当利用酰胺-酯取代将有助于膜渗透性肽的开发。具有高膜渗透性的天然存在的肽通常具有骨架酯键。在这里，作者研究了酰胺-酯取代对肽的膜渗透性的影响，发现该取代对改善环肽的膜渗透性是有用的。
Naturally occurring peptides with high membrane permeability often have ester bonds on their backbones. However, the impact of amide-to-ester substitutions on the membrane permeability of peptides has not been directly evaluated. Here we report the effect of amide-to-ester substitutions on the membrane permeability and conformational ensemble of cyclic peptides related to membrane permeation. Amide-to-ester substitutions are shown to improve the membrane permeability of dipeptides and a model cyclic hexapeptide. NMR-based conformational analysis and enhanced sampling molecular dynamics simulations suggest that the conformational transition of the cyclic hexapeptide upon membrane permeation is differently influenced by an amide-to-ester substitution and an amide N-methylation. The effect of amide-to-ester substitution on membrane permeability of other cyclic hexapeptides, cyclic octapeptides, and a cyclic nonapeptide is also investigated to examine the scope of the substitution. Appropriate utilization of amide-to-ester substitution based on our results will facilitate the development of membrane-permeable peptides. Naturally occurring peptides with high membrane permeability often have backbone ester bonds. Here, the authors investigated the effect of an amide-to-ester substitution on membrane permeability of peptides and found the substitution is useful for improving membrane permeability of cyclic peptides.
登录
查看更多内容
影响因子：
2.1
作者：
Biron, E;Chatterjee, J;Kessler, H
通讯作者：
Kessler, H
影响因子：
7.3
作者：
Klein VG;Bond AG;Craigon C;Lokey RS;Ciulli A
通讯作者：
Ciulli A
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
16.6
作者：
Biron, Eric;Chatterjee, Jayanta;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
4.2
作者：
Klein, Victoria G.;Townsend, Chad E.;Lokey, R. Scott
通讯作者：
Lokey, R. Scott