title: Design of small molecules targeting I-BAR proteins.
abstract: Missing in metastasis (MIM, also MTSS1) is a member of the inverse Bin-Amphiphysin-Rvs (I-BAR) family that senses and stabilizes negative membrane protrusions. Abnormal expression of MIM has been frequently associated with a subset of human cancers and may play different roles in different stages of tumor progression. Overexpression of MIM-I-BAR in 293A cells potentiated the cell growth and increased the toxic response to paclitaxel. To modulate the function of MIM within cells, we designed several short peptide derivatives to target I-BAR dimerization. One of these derivatives had a cyclic configuration with a potency to disrupt the dimerization of MIM or ABBA proteins in vitro, and to be readily internalized into cells. Exposure of cells expressing MIM-I-BAR to this compound abolished increased susceptibility to paclitaxel and partially inhibited the IBAR- mediated endocytosis. Our data suggests that this cyclic peptide can be used as a tool to study the function of intracellular MIM and as a lead to develop a therapy targeting human diseases involving abnormal MIM expressions.
authors.forename: Meng
authors.initials: M
authors.lastname: Cao
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chang
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.forename: Junqing
authors.initials: J
authors.lastname: Chen
authors.forename: Xi
authors.initials: X
authors.lastname: Zhan
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, PR China. jimin@seu.edu.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000639:trends*; D015195:Drug Design; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins