Isoleucine/leucine residues at “a” and “d” positions of a heptad repeat sequence are crucial for the cytolytic activity of a short anticancer lytic peptide

详细信息    查看全文

• 作者：Ruru Fan ; Yanyan Yuan ; Qiang Zhang ; Xi-Rui Zhou ; Lili Jia ; Zhuqing Liu&#8230
• 关键词：Anticancer lytic peptide ; Heptad sequence ; Peptide–membrane interaction ; Cytolytic activity ; Peptide design
• 刊名：Amino Acids
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：49
• 期：1
• 页码：193-202
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biochemistry, general; Analytical Chemistry; Biochemical Engineering; Life Sciences, general; Proteomics; Neurobiology;
• 出版者：Springer Vienna
• ISSN：1438-2199
• 卷排序：49

文摘

Many lytic peptides contain a heptad sequence with leucine or isoleucine residues at “a” and “d” positions. However, their roles in the peptide-induced cytolytic process remain unclear. We have recently reported an anticancer lytic peptide ZXR-2 (FKIGGFIKKLWRSLLA), which contains a shortened zipper-like sequence with Ile/Leu at “a” and “d” positions. To understand the roles of these Ile/Leu residues, a series of analogs were constructed by sequentially replacing the Ile or Leu residue with alanine (Ala). Significant reduction of the cytolytic activity was observed when the Ile (3rd and 7th) and Leu (10th and 14th) residues at the “a” and “d” positions were substituted, while the replacement of the separate Leu (15th) residue had less effect. Based on the quenching of the intrinsic fluorescence of the peptides and their induced surface pressure changes of lipid monolayer, it was conjectured that the peptide ZXR-2 might insert into cell membranes from the C-terminal and to a depth of the W₁₁ position. Accordingly, I₃, I₇, and L₁₀ residues which mainly exposed in aqueous solution were more responsible for the peptide self-association on cell membranes, while L₁₄, together with L₁₅, might help peptide insert and anchor to cell membranes. These results are significant to elucidate the crucial roles of such Ile/Leu residues at “a” and “d” positions in peptide–peptide and peptide–membrane interactions to exert the membrane disruption activity of lytic peptides. With further understanding about the structure–activity relationship of lytic peptides, it would be helpful for designing novel anticancer lytic peptides.