多价环肽偶联药物的设计与合成

Peptide-Drug Conjugate (PDC) plays an important role in anti-tumor drug design. Because of the high specificity and low immunoresponse, PDC becomes popular in novel anti-tumor drug development recently. However, a PDC may have instability in vivo, poor cell-penetrating property, and individual molecular target which could cause drug resistance. These disadvantages could limit the applications of PDC. To solve these problems, this proposal will focus on the multivalent target, which is HER1 (Human Epidermal growth factor Receptor 1) and HER2 (Human Epidermal growth factor Receptor 2) heterodimer. The multiple targets could increase the interaction between drug and biomarkers. Moreover, cyclic peptide, which is stable and cell-penetrable, is used to substitute the linear peptide. We will also investigate the biosynthesis approach for this relatively long peptide to reduce the cost, followed by the chemical modification to obtain the multivalent cyclic PDC (mcPDC) molecule. The biological function and the molecular mechanism of mcPDC will be studied to evaluate the drug. This brand new design of mcPDC might open up a new avenue to investigate the anti-tumor drugs.

以肿瘤为靶点的多肽偶联药物（Peptide-Drug Conjugate，PDC），因具备良好的靶向性与低免疫原性而发展迅速。但是，多肽偶联药物在应用中存在一定的弊端。例如多肽稳定性、细胞通透性差，导致药物在体内的半衰期短，且输送困难；药物的靶点单一，容易引起耐药性。针对多肽偶联药物的不足，本项目以肿瘤细胞表面HER1（人类表皮生长因子受体1）与HER2（人类表皮生长因子受体2）蛋白异源二聚体等为靶点，拟设计合成多价环肽偶联药物（Multivalent Cyclic Peptide-Drug Conjugate，mcPDC）。即采用环肽代替线性多肽，以增加药物稳定性与细胞通透性；组合二种靶向环肽形成多价环肽偶联药物，以增强分子识别；并对合成的药物分子进行生物学评价。在合成方法中，拟采取生物合成与化学修饰相结合的手段，降低多肽合成的难度和成本。本项目将为多肽偶联药物的设计和应用开辟新的途径。

以肿瘤为靶点的多肽偶联药物（Peptide-Drug Conjugate，PDC），因具备良好的靶向性与低免疫原性而发展迅速。但是，多肽偶联药物在应用中存在一定的弊端。例如多肽稳定性、细胞通透性差，导致药物在体内的半衰期短，且输送困难；药物的靶点单一，容易引起耐药性。针对多肽偶联药物的不足，本项目以肿瘤细胞表面HER1（人类表皮生长因子受体1）与HER2（人类表皮生长因子受体2）蛋白异源二聚体等为靶点，拟设计合成多价环肽偶联药物（Multivalent Cyclic Peptide-Drug Conjugate，mcPDC）。即采用环肽代替线性多肽，以增加药物稳定性与细胞通透性；组合二种靶向环肽形成多价环肽偶联药物，以增强分子识别；并对合成的药物分子进行生物学评价。在合成方法中，拟采取生物合成与化学修饰相结合的手段，降低多肽合成的难度和成本。本项目将为多肽偶联药物的设计和应用开辟新的途径。

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