Studies on the Design and Activity of Anticancer Peptides Based on the Weak Acidic Microenvironment of Tumors
10.13865/j.cnki.cjbmb.2025.09.1275
- VernacularTitle:基于肿瘤弱酸性微环境的抗癌肽设计及其活性研究
- Author:
Yue-Qi NIE
1
;
Miao JIANG
;
Hui-Yan WU
;
Chang-Hao DING
;
Wei REN
;
Jun-Yi CHANG
;
Ke CHEN
;
Shao-Long DU
;
Peng ZHANG
;
Zhong-Hua LIU
Author Information
1. 湖南师范大学生命科学学院动物多肽药物创制国家地方联合工程实验室,长沙 410081
- Publication Type:Journal Article
- Keywords:
anticancer peptides;
weakly acidic tumor microenvironment;
amino acid substitution;
phys-icochemical properties
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(10):1380-1391
- CountryChina
- Language:Chinese
-
Abstract:
Lung cancer poses a serious threat to global public health security.Chemotherapy,as the main strategy for cancer treatment,faces challenges such as high toxicity and drug resistance.Anticancer peptides have the potential of being developed into new anticancer drugs due to their advantages of broad-spectrum anticancer activity,rapid action,and difficulty in generating drug resistance,but they also face shortcomings such as weak activity and strong toxic side effects.The weakly acidic microenvironment of tumors(pH 6.5-6.8)provides a good idea for the design of anticancer peptides of high-efficiency and low-toxicity.Previously,we designed the acid-sensitive antibacterial peptide pHly-1 using the wolf spider(Lycosa singoriensis)toxin Lycosin-Ⅰ as a template.In this study,we found that pHly-1 also had acid-sensitive anticancer activity.Further alanine scanning analysis of pHly-1 was carried out,and we ob-tained a mutant pHTP-2 with better acid sensitivity,whose IC50(half maximal inhibitory concentration)against A549 cells was 15.68 μmol/L at pH 6.6 and was greater than 100 μmol/L at pH 7.4.At pH 6.6,pHTP-2 could act on various lung cancer cell lines and induce the death of A549 cells by rapid ly-sis;at pH 7.4,500 μmol/L pHTP-2 had weak toxicity to red blood cells(the hemolysis rate was ap-proximately 38％)and primary myocardial cells(the inhibition rate was 49.7％,with P＜0.05).Analy-sis of its charge,particle size,morphology,and secondary structure showed that at pH 6.6,the histidine in the sequence of pHTP-2 was protonated,increasing the positive charge(P＜0.01),decreasing the hy-drated particle size(P＜0.05)and forming an α-helical structure to induce membrane lysis of A549 cells.At pH 7.4,it was deprotonated,the positive charge decreases,a β-sheet structure was formed and self-aggregation occurred,limiting its effect on the A549 cell membrane and showing weak activity.In summary,pHTP-2 could respond to the weakly acidic microenvironment of tumors to exert selective cyto-toxic activity,effectively overcoming the shortcomings of anticancer peptides such as low efficiency and high toxicity.Our findings suggest that it is a high-quality lead molecule for anticancer drugs.
