Design and synthesis of TH19P01-Camptothecin based hybrid peptides inducing effective anticancer responses on sortilin positive cancer cells

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-08-03 DOI:10.1016/j.bmc.2024.117869

Ya-Jie Li , Chang-Bo Fang , Shu-Shu Wang , Xin-Qi Chen , Yantao Li , Qing Liu , Yun-Kun Qi , Shan-Shan Du

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Abstract

Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based “turn on” hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.

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设计和合成基于 TH19P01-喜树碱的混合肽，诱导索氏林阳性癌细胞产生有效的抗癌反应。

最近，人们发现许多癌细胞表面优先过度表达 SORT1 受体，这使 SORT1 成为一个新的抗癌靶点。SORT1 结合专有肽 TH19P01 可以实现 SORT1 介导的癌细胞结合和随后的内化。受多肽-药物共轭物（PDC）策略的启发，本研究设计、高效合成了 TH19P01-喜树碱（CPT）共轭物，并对其抗癌潜力进行了评估。研究系统地评估了这些共轭物的水溶性、体外抗癌活性、时间杀伤动力学、细胞摄取、抗迁移活性和溶血效应。此外，为了实时监测CPT从共轭物中的释放，还设计了基于CPT/Dnp的 "开启 "混合肽，结果表明CPT可在人血清和癌细胞环境中从混合肽中持续释放。引人注目的是，与游离的 CPT 相比，杂交肽 LYJ-2 的水溶性、细胞摄取性和对癌细胞的选择性都显著提高。此外，与游离的 CPT 或 TH19P01 不同，LYJ-2 对 SORT1 阳性的 MDA-MB-231 细胞具有选择性的抗增殖和抗迁移作用。总之，这项研究不仅建立了提高化疗药物 CPT 溶解性和抗癌潜力的有效策略，还为今后开发基于 TH19P01 的靶向 SORT1 的 PDCs 提供了重要参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.