PDF(Pubmed)
Abstract：
As the least abundant residue in proteins, tryptophan widely exists in peptide drugs and bioactive natural products and contributes to drug-target interactions in multiple ways. We report here a clickable tryptophan modification for late-stage diversification of native peptides, via catalyst-free C2-sulfenylation with 8-quinoline thiosulfonate reagents in trifluoroacetic acid (TFA). A wide range of groups including trifluoromethylthio (SCF3), difluoromethylthio (SCF2H), (ethoxycarbonyl)difluoromethylthio (SCF2CO2Et), alkylthio, and arylthio were readily incorporated. The rapid reaction kinetics of Trp modification and full tolerance with other 19 proteinogenic amino acids, as well as the super dissolving capability of TFA, render this method suitable for all kinds of Trp-containing peptides without limitations from sequences, hydrophobicity, and aggregation propensity. The late-stage modification of 15 therapeutic peptides (1.0 to 7.6 kilodaltons) and the improved bioactivity and serum stability of SCF3- and SCF2H-modified melittin analogs illustrated the effectiveness of this method and its potential in pharmacokinetic property improvement.
摘要：
作为蛋白质中最不丰富的残基，色氨酸广泛存在于多肽药物和生物活性天然产物中，并以多种方式促进药物与靶标的相互作用。我们在这里报告了可点击的色氨酸修饰，用于天然肽的后期多样化，通过用8-喹啉硫代磺酸盐试剂在三氟乙酸(TFA)中的无催化剂的C2-次磺酰化。广泛的基团，包括三氟甲硫基（SCF3），二氟甲硫基(SCF2H),（乙氧基羰基）二氟甲硫基（SCF2CO2Et），烷硫基，和芳硫基容易掺入。Trp修饰的快速反应动力学和对其他19种蛋白质氨基酸的完全耐受性，以及TFA的超强溶解能力，使该方法适用于所有类型的含Trp的肽，而不受序列的限制，疏水性,和聚集倾向。15种治疗性肽（1.0至7.6千道尔顿）的后期修饰以及SCF3-和SCF2H修饰的蜂毒素类似物的生物活性和血清稳定性的改善说明了该方法的有效性及其在药代动力学性质改善中的潜力。
