文献类型：期刊文献

英文题名：Mitochondrial Voltage-Dependent Anion Channel 1-Hexokinase-II Complex-Targeted Strategy for Melanoma Inhibition Using Designed Multiblock Peptide Amphiphiles

作者：Zhang, Fan[1];Angelova, Angelina[2];Garamus, Vasil M.[3];Angelov, Borislav[4];Tu, Shuyang[5];Kong, Liangliang[5];Zhang, Xinlei[1];Li, Na[5];Zou, Aihua[1,6]

机构：[1]East China Univ Sci & Technol, Sch Chem & Mol Engn, Shanghai Key Lab Funct Mat Chem, Shanghai 200237, Peoples R China;[2]Univ Paris Saclay, Inst Galien Paris Saclay UMR8612, CNRS, F-92290 Chatenay Malabry, France;[3]Helmholtz Zentrum Hereon, D-21502 Geesthacht, Germany;[4]Acad Sci Czech Republ, Inst Phys, ELI Beamlines, CZ-18221 Prague, Czech Republic;[5]Chinese Acad Sci, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Zhangjiang Lab, Shanghai 201210, Peoples R China;[6]Shanghai Normal Univ, Coll Chem & Mat Sci, Shanghai 200234, Peoples R China

年份：2021

卷号：13

期号：30

起止页码：35281

外文期刊名：ACS APPLIED MATERIALS & INTERFACES

收录：;EI(收录号：20213310780962);WOS:【SCI-EXPANDED(收录号:WOS:000683741400004)】；

基金：This work was supported by the National Natural Science Foundation of China (nos. 21872051 and 21573070) and the projects "Structural dynamics of biomolecular systems" (ELIBIO) (CZ.02.1.01/0.0/0.0/15_003/0000447) and "Advanced research using high-intensity laser produced photons and particles" (CZ.02.1.01/0.0/0.0/16_019/0000789) (ADONIS) from the European Regional Development Fund.

语种：英文

外文关键词：VDAC1-derived amphiphilic peptides; self-assembly; mitochondria-mediated apoptosis; targeting VDAC1-HK-II complex; protein-protein interaction inhibition; cell-penetrating peptides (CPP); human melanoma cells

摘要：Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial a-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.