紫杉醇水凝胶成胶因子延缓微管蛋白聚集

Paclitaxel Hydrogelator Delays Microtubule Aggregation

紫杉醇是最有效的抗癌药物之一，其机理主要是通过与序一微倚蛋白结合，抑制微管解聚．我们前期工作表明，紫杉醇的水凝胶成胶因子Fmoc—Phe—Phe—Lys（PTx）-Tyr（H2PO3）-OH能够促进神经元分支化，但其机理不详．本文通过微管蛋白体外组装一解组装实验，发现化合物Fmoc—Phe—Phe—Lys（PTx）-Tyr（H2PO3）-OH（1）比紫杉醇有着更明显的延缓微管蛋白聚集的作用．化合物1在碱性磷酸酶的作用下形成Fmoc—Phe—Phe—Lys（PTx）-Tyr-OH纳米纤维，其直径与微管蛋白二聚体的尺寸相当．由此推测这种纳米纤维不仅抑制了微管蛋白二聚体的相互聚集，而且干扰了微管正端微管蛋白的聚集．本：工作提供了一个紫杉醇衍生物成胶因子抑制微管聚集的新原理．

Paclitaxel （PTX） is one of the most efficient anticancer drugs for the treatment of cancers through β-tubulin-binding. Our previous work indicated that a PTX-derivative hydrogelator Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr（H2PO3）-OH （1）could promote neuron branching but the underlying mechanism remains unclear. Using tubulin assembly-disassembly assay, in this work, we found that compound 1 obviously delayed more microtubule aggregation than PTX did. Under the catalysis of alkaline phosphatase, Fmoc-Phe-Phe-Lys（paclitaxel）- Tyr（H2PO3）-OH could self-assemble into nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH with width comparable to the size of αβ-tubulin dimer. Therefore, we proposed in this work that nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH not only inhibits the αβ-tubulin dimer binding to each other but also interferes with the plus end aggregation of microtubule. This work provides a new mechanism of the inhibition of microtubule formation by a PTX- derivative hydrogelator.