Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, United States of America.
Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America.
PLoS One. 2018 Jun 28;13(6):e0199686. doi: 10.1371/journal.pone.0199686. eCollection 2018.
Peptides that exhibit enzymatic or hormonal activities are regulatory factors and desirable therapeutic drugs because of their high target specificity and minimal side effects. Unfortunately, these drugs are susceptible to enzymatic degradation, leading to their rapid elimination and thereby demanding frequent dosage. Structurally modified forms of some peptide drugs have shown enhanced pharmacokinetics, improving their oral bioavailability. Here, we discuss a novel glycomimetic approach to modify lysine residues in peptides. In a model system, the ε-amine of Ts-Lys-OMe was reductively alkylated with a glucose derivative to afford a dihydroxylated piperidine in place of the amine. A similar modification was applied to H-KPV-NH2, a tripeptide derived from the α-melanocyte stimulating hormone (α-MSH) reported to have antimicrobial and anti-inflammatory properties. Antimicrobial assays, under a variety of conditions, showed no activity for Ac-KPV-NH2 or the α- or ε-glycoalkylated analogs. Glycoalkylated peptides did, however, show stability toward proteolytic enzymes.
具有酶或激素活性的肽是调节因子和理想的治疗药物，因为它们具有高度的靶标特异性和最小的副作用。不幸的是，这些药物容易被酶降解，导致它们迅速消除，因此需要频繁给药。一些肽药物的结构修饰形式显示出增强的药代动力学特性，提高了它们的口服生物利用度。在这里，我们讨论了一种修饰肽中赖氨酸残基的新型糖模拟方法。在模型系统中，Ts-Lys-OMe 的 ε-胺与葡萄糖衍生物发生还原烷基化反应，生成取代胺的二羟基哌啶。类似的修饰也应用于 H-KPV-NH2，这是一种三肽，来源于 α-促黑素细胞激素 (α-MSH)，据报道具有抗菌和抗炎特性。在各种条件下的抗菌测定中，Ac-KPV-NH2 或 α-或 ε-糖基化类似物均没有活性。然而，糖基化肽对蛋白水解酶具有稳定性。
