From a pro-apoptotic peptide to a lytic peptide: One single residue mutation
Xi-Rui Zhou, Qiang Zhang, Xi-Bo Tian, Yi-Meng Cao, Zhu-Qing Liu, Ruru Fan, Xiu-Fang Ding, Zhentai Zhu, Long Chen, Shi-Zhong Luo
Biochimica et Biophysica Acta (BBA) - Biomembranes
Further discovery and design of new anticancer peptides are important for the development of anticancer therapeutics, and study on the detailed acting mechanism and structure-function relationship of peptides is critical for anticancer peptide design and application. In this study, a novel anticancer peptide ZXR-1 (FKIGGFIKKLWRSKLA) derived from a known anticancer peptide mauriporin was developed, and a mutant ZXR-2 (FKIGGFIKKLWRSLLA) with only one residue difference at the 14th position (Lys → Leu) was also engineered. Replacement of the lysine with leucine made ZXR-2 more potent than ZXR-1 in general. Even with only one residue mutation, the two peptides displayed distinct anticancer modes of action. ZXR-1 could translocate into cells, target on the mitochondria and induce cell apoptosis, while ZXR-2 directly targeted on the cell membranes and caused membrane lysis. The variance in their acting mechanisms might be due to the different amphipathicity and positive charge distribution. In addition, the two Ile-Leu pairs (3–10 and 7–14) in ZXR-2 might also play a role in improving its cytotoxicity. Further study on the structure-function relationship of the two peptides may be beneficial for the design of novel anticancer peptides and peptide based therapeutics.
Circular dichroism, Secondary structure, Vesicle interactions, Biochemistry