Design of a Cyclotide Antagonist of Neuropilin-1 and -2 That Potently Inhibits Endothelial Cell Migration

Getz, Jennifer A.; Cheneval, Olivier; Craik, David J.; Daugherty, Patrick S.

doi:10.1021/cb4000585

Cited by 74 publications

(70 citation statements)

References 38 publications

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“…The modeling studies also indicate that under some circumstances a cyclic peptide could fit into the binding pocket (24). Indeed, peptides built on a thermostable, protease-resistant cyclotide kalata B1 scaffold have been described that are thought to interact with NRP-1 as intact cyclic peptides (26). These modeling studies provide a basis for in silico screening of CendR analogs and evaluation of low molecular weight compounds resulting from high throughput screening.…”

Section: Tumor-penetrating Peptidesmentioning

confidence: 99%

Tumor-Penetrating Peptides

Teesalu¹,

Sugahara²,

Ruoslahti³

2013

Front. Oncol.

170

159

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Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC), contains the integrin-binding RGD motif. RGD mediates tumor-homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR) motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular “zip code” of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies, and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is present in the blood.

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Section: Tumor-penetrating Peptidesmentioning

confidence: 99%

Tumor-Penetrating Peptides

Teesalu¹,

Sugahara²,

Ruoslahti³

2013

Front. Oncol.

170

159

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“…Numerous studies have detailed the successful incorporation of linear bioactive peptides grafted onto the cyclotide framework, resulting in improved stability while maintaining potency and selectivity for their targets (Poth et al, 2013). In addition to rational design, high-throughput screening approaches that build combinatorial libraries of cyclotide analogs are being used for drug lead selection (Austin et al, 2009;Getz et al, 2011Getz et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

Henriques

Huang

Chaousis

et al. 2015

Chemistry & Biology

108

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Cyclotides combine the stability of disulfide-rich peptides with the intracellular accessibility of cell-penetrating peptides, giving them outstanding potential as drug scaffolds with an ability to inhibit intracellular protein-protein interactions. To realize and optimize the application of cyclotides as a drug framework and delivery system, we studied the ability of the prototypic cyclotide, kalata B1, to enter mammalian cells. We show that kalata B1 can enter cells via both endocytosis and direct membrane translocation. Both pathways are initiated by targeting phosphatidylethanolamine phospholipids at the cell surface and inducing membrane curvature. This unusual approach to initiate internalization might be harnessed to deliver drugs into cells and, in particular, cancer cells, which present a higher proportion of surface-exposed phosphatidylethanolamine phospholipids. Our findings highlight the potential of these peptides as drug leads for the modulation of traditionally "undruggable" targets, such as intracellular protein-protein interactions.

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“…Yeast 22 and bacterial 23, 24 display systems have been developed for the screening of libraries of other constrained peptide scaffolds such as those based on cystine knots. Adapting these systems to lasso peptides is challenging because the N-terminus of the lasso peptide disappears during its maturation.…”

Section: Resultsmentioning

confidence: 99%

Construction of Lasso Peptide Fusion Proteins

2015

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Lasso peptides are a family of ribosomally-synthesized and posttranslationally-modified peptides (RiPPs) typified by an isopeptide-bonded macrocycle between the peptide N-terminus and an aspartate or glutamate sidechain. The C-terminal portion of the peptide threads through the N-terminal macrocycle to give the characteristic lasso fold. Because of the inherent stability, both proteolytic and often thermal, of lasso peptides, we became interested in whether proteins could be fused to the free C-terminus of lasso peptides. Here we demonstrate fusion of two model proteins, the artificial leucine zipper A1 and the superfolder variant of GFP, to the C-terminus of the lasso peptide astexin-1. Successful lasso cyclization of the N-terminus of these fusion proteins requires a flexible linker in between the C-terminus of the lasso peptide and the N-terminus of the protein of interest. The ability to fuse lasso peptides to a protein of interest is an important step toward phage and bacterial display systems for the high-throughput screening of lasso peptide libraries for new functions.

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Design of a Cyclotide Antagonist of Neuropilin-1 and -2 That Potently Inhibits Endothelial Cell Migration

Cited by 74 publications

References 38 publications

Tumor-Penetrating Peptides

Tumor-Penetrating Peptides

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

Construction of Lasso Peptide Fusion Proteins

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