Cell penetrating peptide
A cell-penetrating peptide (engl. Cell-penetrating peptide , CPP, or protein transduction domain , transduction domain , PTD) denotes a peptide , the cell membranes penetrate through (penetrate) can. As a result, a fusion protein attached to the peptide , as well as nucleic acids or nanoparticles connected covalently or non-covalently to the cell-penetrating peptide , can be introduced into cells . With cell-penetrating peptides, small molecules such as cytostatics , antivirals , contrast media or even quantum dots were brought into cells.
This protein transduction was discovered simultaneously by two research groups in 1988 when it was discovered that the Tat protein of the human immunodeficiency virus (HIV) was taken up by different cell types in cell culture . Since then, further examples of the CPP have become known. Even with polycationic proteins, such as. B. antibodies directed against DNA or histones could be shown uptake in cells.
mechanism
Most cell-penetrating peptides consist mainly of basic and non-polar amino acids , especially lysine and arginine , tryptophan , phenylalanine , leucine and isoleucine ( polycationic type). The cationic amino acids bind to negatively charged receptors on the cell surface, e.g. B. sialic acids or heparan sulfate , while the non-polar amino acids mediate adsorption to the lipids of the cell membrane. Another type consists of alternating polar and non-polar amino acids ( amphipathic type).
Cell-penetrating peptides have different sequences and there are three hypotheses as to how cell penetration occurs:
- via direct penetration of the cell membrane through pore formation
- via hygroscopic buffer effects ( proton sponge ), which after endocytosis lead to swelling of the endosome and tears in the endosome membrane .
- via membrane insertion and the formation of inverted micelles
In some cases, the binding to cells and the endocytosis is increased by binding to receptors , e.g. B. chemokine receptors , syndecans, neuropilins, or integrins . After cell penetration occurred even without endocytosis at 4 ° C, direct penetration , as well as endocytosis- and ATP- independent penetration, was suspected, but artifacts of fixation and staining were also reported. The fact that CPP can also be distributed through ER membranes or artificial lipid bilayers speaks in favor of direct penetration . The formation of a membrane pore on the endosomal membrane or the cell membrane has been verified experimentally. However, an uneven distribution of the CPP in different cell compartments, a reduction in the distribution of the CPP penetratin when endocytosis inhibitors are added, a microscopic colocalization with caveolin and an uptake via pinocytosis speak in favor of endocytosis . It is possible that more than one uptake mechanism is running in parallel; in particular, the proportions of these mechanisms change when the size of the attached molecule or particle changes. The third mechanism presumes the formation of an inverted micelle in which the phosphate groups of the membrane lipids around the CPP and the aliphatic components are oriented outwards. This leaves the peptide in a hydrophilic environment.
Typical representatives of the cell-penetrating peptides are z. B. Penetratin, Transportan, HIV1 Tat peptide 48-60 , HIV1 Rev peptide 34-50 , Antennapedia 43-58, and octaarginine.
Applications
Cell-penetrating peptides can be used in research and therapy as transfection reagents for the transport of RNA, DNA, PNA and morpholinos . Cyclic octaarginines were used for the endocytosis-independent transport of antigen-binding proteins. Modified CPP constructions can be activated by special enzymes such as MMP or by photonic signals and thus enable the targeted transfection of certain cell types .
Cell-penetrating peptides can be coupled to nucleic acids through various bonds, including cleavable linkers, e.g. B. with disulfide bridges , amides , thiazolidine , oximes and hydrazines . However, these groups are believed to have an impact on biological activity . Therefore non-covalent methods of connection between CPP and nucleic acids are also used. Covalent and non-covalent methods were used with siRNA . Likewise, CPP with anti-competitive DNA, plasmids , proteins, contrast agents , quantum dots , gadolinium complexes and superparamagnetic iron oxide (SPIO) were used.
Overview literature
- Siegmund Reissmann: Cell penetration: scope and limitations by the application of cell-penetrating peptides. In: Journal of Peptide Science. 20, 2014, p. 760, doi : 10.1002 / psc.2672 .
- A. Erazo-Oliveras, N. Muthukrishnan, et al. a .: Improving the endosomal escape of cell-penetrating peptides and their cargos: strategies and challenges. In: Pharmaceuticals. Volume 5, number 11, November 2012, pp. 1177-1209, doi : 10.3390 / ph5111177 , PMID 24223492 , PMC 3816665 (free full text) (review).
Web links
- Instant insight into cell penetrating peptides from the Royal Society of Chemistry
- www.cell-penetrating-peptides.com Fully dynamic web page built by scientists to condense and organize the latest advances on drug delivery and Cell-Penetrating Peptides
- CPPsite : A web site for maintaining cell penetrating peptides (CPP)
Individual evidence
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