Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn , Brühler Str. 7, 53119 Bonn, Germany.
J Med Chem. 2014 Dec 26;57(24):10355-65. doi: 10.1021/jm501058g. Epub 2014 Dec 5.
The inhibition of the final step in blood coagulation, the factor XIIIa (FXIIIa) catalyzed cross-linking of fibrin monomers, is currently still a challenge in medicinal chemistry. We report synthesis, recombinant expression, disulfide connectivity, and biological activity of tridegin, the sole existing peptide representative displaying inhibitory activity on FXIIIa. Inhibition of the enzyme by this 66-mer cysteine-rich peptide is mediated by its C-terminal sequence, while the N-terminal part comprises structural information and contributes to inhibitor binding. Either of the production strategies examined leads to the formation of different disulfide-bridged isomers indicating the requirement of the correct fold for inhibitory activity. Molecular modeling and docking studies confirm disulfide bond isomer preference with respect to binding to FXIIIa, in turn, the knowledge of the enzyme-inhibitor interactions might bring about comprehensive ideas for the design of a suitable lead structure for addressing FXIIIa.
目前，抑制血液凝固的最后一步，即因子 XIIIa（FXIIIa）催化纤维蛋白单体的交联，仍然是药物化学领域的一个挑战。我们报告了 tridegin 的合成、重组表达、二硫键连接和生物学活性，它是唯一具有 FXIIIa 抑制活性的现有肽代表。这种 66 -mer 富含半胱氨酸的肽通过其 C 末端序列抑制酶的活性，而 N 末端部分包含结构信息并有助于抑制剂结合。所检查的两种生产策略都会导致形成不同的二硫键桥接异构体，表明需要正确的折叠才能具有抑制活性。分子建模和对接研究证实了二硫键异构体与 FXIIIa 结合的偏好性，反过来，对酶-抑制剂相互作用的了解可能会为设计合适的 FXIIIa 先导结构提供全面的思路。
