Structural modification of the tripeptide KPV by reductive “glycoalkylation” of the lysine residue

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.

具有酶促活性或激素活性的肽类是一类重要的调控因子，同时也是极具应用前景的治疗药物——因其具备极高的靶点特异性与极低的副作用。遗憾的是，这类药物极易发生酶促降解，导致其被快速清除，因此需要频繁给药。部分经过结构修饰的肽类药物已被证实可优化药代动力学特性，提升口服生物利用度。本文探讨了一种全新的糖模拟修饰策略，用于修饰肽链中的赖氨酸残基。在模型体系中，研究人员以葡萄糖衍生物为修饰试剂，通过还原烷基化反应将Ts-Lys-OMe的ε-氨基转化为二羟基化哌啶结构，以替代原有的氨基。我们将该修饰策略应用于H-KPV-NH₂——一种源自α-促黑素细胞激素（α-melanocyte stimulating hormone，α-MSH）的三肽，据报道该三肽具备抗菌与抗炎活性。在多种实验条件下开展的抗菌活性检测结果显示，Ac-KPV-NH₂及其α-或ε-糖烷基化修饰类似物均未表现出抗菌活性。不过，经糖烷基化修饰的肽类确实展现出了更强的蛋白水解酶稳定性。