A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer

Sohn, Yang Sung; Losub-Amir, Anat; Cárdenas, Alfredo E.; Yahana, Merav Darash; Gruman, Tal; Rowland, Linda M.; Marjault, Henri‐Baptiste; Webb, Lauren J.; Mittler, Ron; Elber, Ron; Friedler, Assaf; Nechushtai, Rachel

doi:10.1039/d2sc01934e

Cited by 12 publications

(27 citation statements)

References 84 publications

(208 reference statements)

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“…NAF-1 44–67 has significant medical promise. It selectively permeates the plasma membrane of malignant but not normal cells . Once it has penetrated the plasma membrane, it also traffics to specific organelles, targeting the MIT and ER but not the nuclear membrane.…”

Section: Introductionmentioning

confidence: 99%

“…It selectively permeates the plasma membrane of malignant but not normal cells. 23 Once it has penetrated the plasma membrane, it also traffics to specific organelles, targeting the MIT and ER but not the nuclear membrane. This remarkable selectivity is further enhanced by the ability of the peptide to kill cancer cells by itself, without carrying additional therapeutic cargo and without damaging normal cells.…”

Section: Introductionmentioning

confidence: 99%

“…This remarkable selectivity is further enhanced by the ability of the peptide to kill cancer cells by itself, without carrying additional therapeutic cargo and without damaging normal cells. 23 Because of the importance of CPPs to medicine, we examine a simplified atomically detailed mechanism as a baseline for investigations of other CPPs. To that end, we examined the permeation of NAF-1 44−67 through a membrane composed of dioleoylphosphatidylcholine (DOPC).…”

Section: Introductionmentioning

confidence: 99%

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Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

et al. 2022

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Cell-penetrating peptides (CPPs) facilitate translocation across biological membranes and are of significant biological and medical interest. Several CPPs can permeate into specific cells and organelles. We examine the incorporation and translocation of a novel anticancer CPP in a dioleoylphosphatidylcholine (DOPC) lipid bilayer membrane. The peptide, NAF-144–67, is a short fragment of a transmembrane protein, consisting of hydrophobic N-terminal and charged C-terminal segments. Experiments using fluorescently labeled NAF-144–67 in ∼100 nm DOPC vesicles and atomically detailed simulations conducted with Milestoning support a model in which a significant barrier for peptide-membrane entry is found at the interface between the aqueous solution and membrane. The initial step is the insertion of the N-terminal segment and the hydrophobic helix into the membrane, passing the hydrophilic head groups. Both experiments and simulations suggest that the free energy difference in the first step of the permeation mechanism in which the hydrophobic helix crosses the phospholipid head groups is −0.4 kcal mol–1 slightly favoring motion into the membrane. Milestoning calculations of the mean first passage time and the committor function underscore the existence of an early polar barrier followed by a diffusive barrierless motion in the lipid tail region. Permeation events are coupled to membrane fluctuations that are examined in detail. Our study opens the way to investigate in atomistic resolution the molecular mechanism, kinetics, and thermodynamics of CPP permeation to diverse membranes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

et al. 2022

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“…In recent years, we have used both experiment and theory to examine the process of small molecule translocation across model membranes. − We previously studied the influence of charge on permeation of the amino acid tryptophan into large, unilamellar vesicles (LUVs) composed of 1,2-dioleoyl- sn -glycero-3-phosphocholine (DOPC) by changing the protonation state on the N- or C-terminus using solution pH. Both experiments and complementary molecular dynamics (MD) simulations revealed that permeation is more favorable for positively charged peptides with ∼10 8 fold more positively charged tryptophan (Trp+) partitioning into the membrane than zwitterionic and negatively charged tryptophan (Trp-), and a lower potential mean force barrier for Trp+ compared to Trp–.…”

Section: Introductionmentioning

confidence: 99%

“…However, other positively charged residues (e.g., lysine) play a similar role. Lys was chosen over Arg because it is relevant to recent work from our laboratories. , While WKW is more positively charged than Trp+, it was not more successful in membrane permeation, requiring elevated temperatures to promote any partitioning into the lipid bilayer. Using MD simulations, we proposed a defect-assisted permeation mechanism for WKW with the local free energy minima of the peptide situated in the plane of either membrane leaflet with its positive charges interacting with the lipid phosphate groups and tryptophan side chains protruding into more hydrophobic regions of the bilayer.…”

Section: Introductionmentioning

confidence: 99%

Design of Peptides for Membrane Insertion: The Critical Role of Charge Separation

et al. 2022

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A physical understanding of membrane permeation and translocation by small, positively charged molecules can illuminate cell penetrating peptide mechanisms of entry and inform drug design. We have previously investigated the permeation of the doubly charged peptide WKW and proposed a defect-assisted permeation mechanism where a small molecule with +2 charge can achieve a metastable state spanning the bilayer by forming a membrane defect with charges stabilized by phospholipid phosphate groups. Here, we investigate the membrane permeation of two doubly charged peptides, WWK and WWWK, with charges separated by different lengths. Through complementary experiments and molecular dynamics simulations, we show that membrane permeation was an order of magnitude more favorable when charges were separated by an ∼2–3 Å greater distance on WWWK compared to WWK. These results agree with the previously proposed defect-assisted permeation mechanism, where a greater distance between positive charges would require a less extreme membrane defect to stabilize the membrane-spanning metastable state. We discuss the implications of these results in understanding the membrane permeation of cell-penetrating peptides and other small, positively charged membrane permeants.

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Peptide‐Based Inhibitors that Target the Docking Site of ERK2

Solomon

Shpilt

Sapir

et al. 2022

Israel Journal of Chemistry

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Abnormal kinase activity is highly associated with disease, especially cancer. Thus, kinases are important targets for developing anti‐cancer drugs. The common approach for kinase inhibition is using small molecules that compete with ATP for binding the ATP‐binding site of the kinase. However, since the ATP‐binding site is in many cases common to numerous kinases, it is difficult to achieve selectivity when targeting this site. Here we present an alternative approach of targeting the protein‐protein interactions of kinases as means for achieving selectivity in their inhibition. We demonstrate this approach by using peptides for inhibiting the docking D‐recruitment site (DRS) of the kinase ERK2. We designed a library of peptides, derived from DRS binding sequences of ERK2‐binding proteins. We synthesized the peptides and quantified their interactions with ERK2. Three peptides, derived from the proteins ELK1, SAP1 and SAP2, bound ERK2 in the low micromolar range. These peptides also inhibited the interaction of ERK2 with a surface‐bound ELK1 derived peptide. The peptides penetrated HT29 colon cancer cells and induced a moderate decrease in cell viability. Our approach can be further utilized for developing selective peptide‐based kinase inhibitors.

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A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer

Abstract: An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance.

Cited by 12 publications

References 84 publications

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

Peptide Permeation across a Phosphocholine Membrane: An Atomically Detailed Mechanism Determined through Simulations and Supported by Experimentation

Design of Peptides for Membrane Insertion: The Critical Role of Charge Separation

Peptide‐Based Inhibitors that Target the Docking Site of ERK2

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