Peptide Ligation at High Dilution via Reductive Diselenide-Selenoester Ligation
Peptide Ligation at High Dilution via Reductive Diselenide-Selenoester Ligation
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DOI：
10.1021/jacs.9b12558
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发表时间：
2020-01-15
影响因子：
15
通讯作者：
Payne, Richard J.
中科院分区：
文献类型：
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作者：
Chisholm, Timothy S.;Kulkarni, Sameer S.;Payne, Richard J.
肽连接化学通过提供均质修饰的肽和蛋白质，彻底改变了蛋白质科学。然而，脂化多肽和完整膜蛋白（一类重要的生物分子）由于在典型连接条件下一个或多个片段的水溶性差，合成获得仍然面临巨大挑战。在此，我们描述了还原二硒化物-硒酯连接（rDSL）方法的出现，该方法能够将肽片段有效连接至低纳摩尔浓度，而无需借助溶解度标签或杂交模板。 rDSL 的强大功能在 FDA 批准的治疗性脂肽 tesamorelin 和跨膜脂蛋白磷酸化蛋白 (FXYD1) 的棕榈酰化变体的有效合成中得到了凸显。 FXYD1 的脂化作用可显着调节 Na+/K+ 泵的抑制活性。
Peptide ligation chemistry has revolutionized protein science by providing access to homogeneously modified peptides and proteins. However, lipidated polypeptides and integral membrane proteins-an important class of biomolecules-remain enormously challenging to access synthetically owing to poor aqueous solubility of one or more of the fragments under typical ligation conditions. Herein we describe the advent of a reductive diselenide-selenoester ligation (rDSL) method that enables efficient ligation of peptide fragments down to low nanomolar concentrations, without resorting to solubility tags or hybridizing templates. The power of rDSL is highlighted in the efficient synthesis of the FDA-approved therapeutic lipopeptide tesamorelin and palmitylated variants of the transmembrane lipoprotein phospholemman (FXYD1). Lipidation of FXYD1 was shown to critically modulate inhibitory activity against the Na+/K+ pump.