title: From a pro-apoptotic peptide to a lytic peptide: One single residue mutation.
abstract: 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.
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xi-Rui
authors.initials: XR
authors.lastname: Zhou
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xi-Bo
authors.initials: XB
authors.lastname: Tian
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Yi-Meng
authors.initials: YM
authors.lastname: Cao
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Zhu-Qing
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Ruru
authors.initials: R
authors.lastname: Fan
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xiu-Fang
authors.initials: XF
authors.lastname: Ding
authors.affiliation: State Key Laboratory of NBC Protection for Civilian, Beijing, China.
authors.forename: Zhentai
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: chenlong@mail.buct.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: luosz@mail.buct.edu.cn.
authors.forename: Shi-Zhong
authors.initials: SZ
authors.lastname: Luo
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008928:Mitochondria / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000737:chemistry; D044967:Serum; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D003603:Cytotoxins; D010455:Peptides; D012604:Scorpion Venoms; C000624237:ZXR-1 peptide; C000624238:ZXR-2 peptide
keywords: Anticancer peptide; Cell apoptosis; Cell lysis; Structure-function relationship