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

Abstract

Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The VDAC1-HK-II complex is an emerging target for novel anti-cancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anti-cancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting.Here, novel multi-block 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 self-assembly propensity and cell-penetrating properties. The created multi-block amphiphilic peptides of partial α-helical conformations formed nanoparticles of ellipsoid-like shapes and were characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane (OMM), which results in mitochondria-mediated apoptosis. The latter was 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 VDAC1derived amphiphilic peptides have a comparable IC 50 value for melanoma cells as the sorafenib small molecule drug, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.

Advances in hybrid peptide-based self-assembly systems and their applications

“…263 Studying the influence of the linker and lipidation on the self-assembly process therefore has an excellent potential for future research. Apart from these, analytical techniques like small-angle X-ray scattering (SAXS) have recently been used for structural analysis of peptide assembly, [264][265][266] and can prove to be a powerful technique for the future. In spite of the points mentioned above, there is still a lot of scope for the design and fabrication of peptides with heterogeneous backbones into supramolecular systems with defined and prominent physical properties.…”

Morphological studies of self-assembled cyclotides extracted fromViola odorataas novel versatile platforms in biomedical applications

“…But, the authors deeply believe that this study introduces the rationale and design concepts of the cyclotide nanotubes, which are likely to find general application in the development of this and related families of peptide-based biomaterials as hollow nanotubes offer enormous scope in designing materials with novel biological properties. [83][84][85][86]…”

Novel Peptide Therapeutic Approaches for Cancer Treatment

“…Significantly, cell death via membrane disruption can result regardless of growth rate or multidrug resistance mechanisms, conditions that often foil conventional chemotherapy approaches, while cationic residues in the peptide can enable preferential targeting of the peptide to the relatively anionic cell membrane of cancer cells. In addition to disrupting the cell membrane, peptides can also disrupt mitochondrial membrane potential resulting in the release of cytochrome c, activation of caspases, and induction of apoptosis [ 77 , 78 , 79 ].…”