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Cell-Penetrating Peptides. Discovery, Structure and Possible Usage in Cancer Treatment

Presentation (Handout) 2015 6 Pages

Chemistry - Organic Chemistry

Excerpt

Different Families of Cell-Penetrating Peptides (CPP‘s)

Definition:

Short peptides (5 - 30 residues in length) with the ability to enter cells independently of a membrane receptor, and without cell-type specifity. They are either cationic or amphiphatic.

Can be distinguished by origin, cargo attachement, and mechanism of entry

Abbildung in dieser Leseprobe nicht enthalten

Types of Cargo and Cargo attachement

Covalent strategy

- chemical cross-linking or cloning followed by expression of a CPP fusion protein
- mainly disulfide or thioester linkages
- different transduction motifs are possible
- used for DNA, peptides, proteins
- procedure reproducible and controlled stoichiometry of the CPP-cargo
- might change the biological activity of the cargo
- CPPs: penetratin, pol-arg, VP22

Non-covalent strategy

- carriers need a hydrophillic and hydrophobic domain (primary or secondary)
- form complexes stable through electrosta- tic and hydrophobic interactions
- often associated with peptides favouring endosomal escape
- used for genes, peptides, proteins
- CPPs: MPG, Pep-1

Mechanism of Uptake

- internalization by energy-dependent vesicular mechanism (endocytosis) or translocating over the lipid bilayer
- depends on the celltype, the attached cargo and the CPP
- 3-step process: 1) membrane interaction, 2) membrane permeation, 3) release of CPP into the cytosol pathways differ from each other in step 2 and 3

Mechanisms of Uptake

Membrane interaction:

- heperan sulfate proteoglycans and syndecans are the major components of the extracellular matrix
- trigger reaction cascade for cellular uptake pathways
- CPPs bind electrostatically at surface proteoglycans glucosaminoglycan (GAG) platform leading to remodelling of the actin network and activation of GTPase Rho A or Rac1
- membrane fluidity is enhanced

Abbildung in dieser Leseprobe nicht enthalten

Potential Applications in Future Cancer Therapie

Cell Targeting Peptides

- molecules with the ability to recognize cancer cells selectively

Abbildung in dieser Leseprobe nicht enthalten

- conjugate of chlorambucil to pVEC-PEGA increases drug efficacy over four times
- transvascular delivery of siRNA to the CNS with a chimeric peptide consisting of rabies virus glycoprotein RVG and a polyarginine CPP at the carboxy terminus
- potential to target brain tumors
- CXC chemokine receptor 4 (CXCR4) over-expressed in 20 different types of cancer
- DV3-TAT-p53C’ (p-53-activating peptide) and DV3-TAT-RxL (cyclin-dependent kinase 2 antagonist) increase efficiency two times as unguided CPPs

Potential Applications in Future Cancer Therapie

Activatable CPP’s (ACCP)

- ACCP/DOX conjugate, sensitive to MMP-2/9 for tumor-targeting
- ACCP includes 3 units:
- polyargenine, R9
- cleavable enzyme-specific substrate domain of MMP-2/9, PLGLAG
- shielding peptide domain, DGGDGGDGGDG

- inactivated in cells lacking MMP-2/9

- after cleavage the CPP-cargo complex is able to penetrate the cell

- uptake and antiproliferative activity is observed

Potential Applications in Future Cancer Therapie

Transducible Agents of CPPs

- many tumors are dissimanated throughout the body
- intraperitoneal injection (IP) of TAT protein leeds to systemic distribution
- tumor cells create a hypoxic microenvironment due to their high metabolic demands
- proliferation is regulated by hypoxia inducible factor-1a (HIF-1a), containing oxygen-dependent degradation domains (ODD)
- wild-type caspase-3 fused to TAT-ODD leads to cell-death in cancer tissue

Summary

- existence of natural proteins with the capability to cross the cell membrane
- CPPs can be tailored and functionalized in order to increase their range of application
- nearly every kind of cargo can be attached, either covalent or by forming a complex
- different mechanism of uptake, endocytosis or direct translocation, do exist
- hard to predict and not fully understood
- various possibilities of potentially applications in cancer therapy or other diseases, but still most of the molecular mechanism is unrevealed

References

1. Green, M.; Loewenstein, P. M., Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 1988, 55 (6), 1179-1188.

2. Harada, H.; Hiraoka, M.; Kizaka-Kondoh, S., Antitumor Effect of TAT-Oxygen-dependent Degradation- Caspase-3 Fusion Protein Specifically Stabilized and Activated in Hypoxic Tumor Cells. Cancer Research 2002, 62 (7), 2013-2018.

3. Heitz, F. et al., Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. British Journal of Pharmacology 2009, 157, 195-206.

4. Patel, L. N.; Zaro, J. L.; Shen, W.-C., Cell Penetrating Peptides: Intracellular Pathways and Pharmaceutical Perspectives. Pharmaceutical Research 2007, 24 (11), 1977-1992.

5. Regberg, J. et al., Applications of Cell-Penetrating Peptides for Tumor Targeting and Future Cancer Therapies. Pharmaceuticals 2012, 5, 991-1007.

6. Sebbage, V., Cell-penetrating peptides and their therapeutic applications. Bioscience Horizons 2009, 2 (1), 64-72.

7. Snyder, E. L.; Dowdy, S. F., Cell Penetrating Peptides in Drug Delivery. Pharmaceutical Research 2004, 21 (3), 389-393.

8. Stewart, K. M. et al., Cell-penetrating peptides as delivery vehicles for biology and medicine. Org. Biomol. Chem. 2008, 6, 2242-2255

11 13.01.2015 Cell-Penetrating Peptides - Development, Molecular Mechanisms, and Therapeutic Applications Universität Konstanz

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Details

Pages
6
Year
2015
ISBN (eBook)
9783668293861
File size
840 KB
Language
English
Catalog Number
v337837
Institution / College
University of Constance – Chemie
Grade
Tags
CPP penetration macropinozytose endozytose

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Title: Cell-Penetrating Peptides. Discovery, Structure and Possible Usage in Cancer Treatment