A Lipidated Peptide with Mitochondrial Membrane Localization in Human A549 Lung Cells: From Enhanced Cell-Penetrating Properties to Biological Activity Mechanism

Abstract

Here, a lipidated peptide Pal-pHK-pKV with self-assembly properties and the ability to provoke the disruption of the mitochondrial voltage-dependent anion channel-1 protein (VDAC1)-hexokinase-II (HK-II) complex is reported. The effects of the peptide pHK (N-terminal 15-amino acid fragment of HK-II that specifically binds VDAC1) are compared to those of a designed biomimetic amphiphilic pHK-pKV conjugate (pHK coupled with a cell-penetrating peptide pKV) and Pal-pHK-pKV (a lipidated conjugate modified with a hydrophobic palmitic (Pal) alkyl chain). The Pal-pHK-pKV exhibits a stronger interaction with the membrane as compared to pHK-pKV, which is demonstrated by the Langmuir–Blodgett technique and two-photon excitation microscopy. The amphiphilic peptide derivatives are cytotoxic to the A549 cells, but Pal-pHK-pKV is more cytotoxic. The inhibitory effects of the pHK derivatives on the A549 cells growth are investigated through induced apoptosis pathway, depolarized mitochondrial membrane potential, inhibited glycolysis, and activated caspase. The results of the immunofluorescence evidence the specific mitochondrial targeting by those derivatives.

Design, synthesis and antifreeze properties of biomimetic peptoid oligomers

“…Peptoids are a new class of peptide mimetic compounds where the side chains on the α-carbons are transferred to main chain nitrogens (Scheme 1). 7 The lack of hydrogen bonds and chiral centers in the backbone endows peptoids with some special properties, such as good resistance to enzymatic degradation, excellent solubility and biocompatibility. 8 Great progress has been made in the preparation methods, structure and property studies of peptoids through decades of development, 9 which enables peptoids to be used in the fields of biomedicine, 10 chemical catalysis 11 and nanomaterials.…”

Membrane targeting with palmitoylated lysine added to PP1‐disrupting peptide induces PP1‐independent signaling

“…It has long been known to be involved with protein trafficking to and from the cellular membrane, as it greatly increases the hydrophobicity of proteins and peptides 17 . The addition of a palmitoyl group to a peptide was shown to enhance its interaction with lipid bilayers and can facilitate the cellular uptake 18–23 . Thus, palmitoylation was selected in order to impart a membrane‐associating functionality to the PDPs, by incorporating palmitic acid into the PDP‐ Nal sequence, the most recently optimized PDP 24 .…”

“…17 The addition of a palmitoyl group to a peptide was shown to enhance its interaction with lipid bilayers and can facilitate the cellular uptake. [18][19][20][21][22][23] Thus, palmitoylation was selected in order to impart a membrane-associating functionality to the PDPs, by incorporating palmitic acid into the PDP-Nal sequence, the most recently optimized PDP. 24 Because the C-terminal side of the PDP sequence contains the RVxF motif and two isoleucines (the ΦΦ motif) that directly associate with the PP1 catalytic subunit, 10 the N-terminal side makes a more logical choice for addition of the palmitate.…”

Small molecules targeting the NADH-binding pocket of VDAC modulate mitochondrial metabolism in hepatocarcinoma cells

“…Research efforts have been also dedicated to disrupt the interaction between VDAC and hexokinase-II as a mechanism to target mitochondrial function for cancer therapy. Recently, it has been shown that a series of cell permeant amphiphilic peptides that disrupt the interaction between VDAC1 and HK-II induce apoptosis in melanoma and lung carcinoma cells [ 45 - 47 ]. From a pharmacological perspective, the success of modulating VDAC opening is most likely to occur if the three isoforms are targeted simultaneously.…”