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

Abstract

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 membrane-lytic 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.

Graphical abstract

Keywords

Antimicrobial peptide / Peptide-drug conjugate / Cell-penetrating activity / Membrane disruption / Antitumor activity

Conflicts of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

This work was 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).

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Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2024.100890.

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