Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy  

作　　者：Sujie Huang Yuxuan Gao Ling Ma Bo Jia Wenhao Zhao Yufan Yao Wenyuan Li Tongyi Lin Rui Wang Jingjing Song Wei Zhang 

机构地区：[1]Institute of Pharmacology,School of Basic Medical Sciences,Lanzhou University,Lanzhou 730000,China [2]Key Laboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences&Research Unit of Peptide Science,Chinese Academy of Medical Sciences,Lanzhou University,Lanzhou 730000,China [3]State Key Laboratory of Veterinary Etiological Biology,College of Veterinary Medicine,Lanzhou University,Lanzhou 730000,China [4]Lanzhou University Second Hospital,Lanzhou University,Lanzhou 730000,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2024年第1期135-146,共12页亚洲药物制剂科学（英文）

基　　金：supported by the grants from the National Natural Science Foundation of China(Nos.81773566 and 21602092);Innovation Project of Medicine and Health Science and Technology of Chinese Academy of Medical Sciences(2019-I2M-5-074);the Funds for Fundamental Research Creative Groups of Gansu Province(No.20JR5RA310);the Fundamental Research Funds for the Central Universities(No.lzujbky-2021-38).

摘　　要：Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

关 键 词：Antimicrobial peptide Peptide-drug conjugate Cell-penetrating activity Membrane disruption Antitumor activity 

分 类 号：R943[医药卫生—药剂学] R737.9[医药卫生—药学]