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Nikita Oskolkov Piret Arukuusk Dana-Maria Copolovici Staffan Lindberg Helerin Margus Kärt Padari Margus Pooga Ülo Langel 《International journal of peptide research and therapeutics》2011,17(2):147-157
Oligonucleotide-based gene regulation has a high potential in gene therapy, but the plasma membrane is impermeable for nucleic
acid polymers and, consequently, an efficient and non-toxic transfection agent is needed for their delivery into the cell.
In this study we present a novel series, NickFects, of chemically modified TP10 peptide-based delivery vectors used for the
cellular delivery of single-stranded oligonucleotides. These carriers, obtained by replacement of Ile8 by threonine in stearyl-TP10
and by modifying of tyrosine and/or threonine, respectively, by phosphorylation formed 300–500 nm in size peptide:oligonucleotide
nanocomplexes with negative surface charges. The highest splice-correcting effect was obtained when phosphorotiate 2′-O-methyl
oligonucleotides were transduced into cells by NickFect1 (NF1) or NickFect2 (NF2). In addition, we also show how a small modification
(one or two negative charges) in peptide sequence can affect its ability to deliver ONs into cells and increase their potency
in the splicing redirection assay. Our studies demonstrate that NF1 and NF2 have higher transfection efficacy for oligonucleotides
as compared to the most commonly used transfection agent Lipofectamine™ 2000 and lead to higher biological response in cells. 相似文献
113.
Several chimeric peptides were synthesized and found to be high-affinity ligands for both galanin and substance P receptors in membranes from the rat hypothalamus. The peptide galantide, composed of the N-terminal part of galanin and C-terminal part of substance P (SP), galanin-(1-12)-Pro-SP-(5-11) amide, which is the first galanin antagonist to be reported, recognizes two classes of galanin binding sites (KD(1) less than 0.1 nM and KD(2) approximately 6 nM) in the rat hypothalamus, while it appears to bind to a single population of SP receptors (KD approximately 40 nM). The chimeric peptide has higher affinity towards galanin receptors than the endogenous peptide galanin-(1-29) (KD approximately 1 nM) or its N-terminal fragment galanin-(1-13) (KD approximately 1 microM), which constitutes the N-terminus of the chimeric peptide. Galantide has also higher affinity for the SP receptors than the C-terminal SP fragment-(4-11) amide (KD = 0.4 microM), which constitutes its C-terminal portion. Substitution of amino acid residues, which is of importance for recognition of galanin by galanin receptors, such as [Trp2], in the galanin portion of the chimeric peptide or substitution of ([Phe7] or [Met11]-amide) in the SP portion of chimeric peptide both cause significant loss in affinity of the analogs of galantide for both the galanin- and the SP-receptors. These results suggest that the high affinity of the chimeric peptide, galantide, may in part be accounted for by simultaneous recognition/binding to both receptors.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
114.
Pernilla Östlund Kalle Kilk Maria Lindgren Mattias Hällbrink Yang Jiang Metka Budihna Katarina Cerne Aljosa Bavec Claes-Göran Östenson Matjaz Zorko Ülo Langel 《International journal of peptide research and therapeutics》2005,11(4):237-247
Cell-penetrating peptides have proven themselves as valuable vectors for intracellular delivery. Relatively little is known
about the frequency of cell-penetrating sequences in native proteins and their functional role. By computational comparison
of peptide sequences, we recently predicted that intracellular loops of G-protein coupled receptors (GPCR) have high probability
for occurrence of cell-penetrating motifs. Since the loops are also receptor and G-protein interaction sites, we postulated
that the short cell-penetrating peptides, derived from GPCR, when applied extracellularly can pass the membrane and modulate
G-protein activity similarly to parent receptor proteins. Two model systems were analyzed as proofs of the principle. A peptide
based on the C-terminal intracellular sequence of the rat angiotensin receptor (AT1AR) is shown to internalize into live cells
and elicit blood vessel contraction even in the presence of AT1AR antagonist Sar1-Thr8-angiotensin II. The peptide interacts with the same selectivity towards G-protein subtypes as agonist-activated AT1AR and
blockade of phospholipase C abolishes its effect. Another cell-penetrating peptide, G53-2 derived from human glucagon-like
peptide receptor (GLP-1R) is shown to induce insulin release from isolated pancreatic islets. The mechanism was again found
to be shared with the original GLP-1R, namely G11-mediated inositol 1,4,5-triphosphate release pathway. These data reveal a novel possibility to mimic the effects of signalling
transmembrane proteins by application of shorter peptide fragments. 相似文献
115.
T Land U Langel M L?w M Berthold A Undén T Bartfai 《International journal of peptide and protein research》1991,38(3):267-272
The neuropeptide galanin (1-29) binds with high affinity to hypothalamic receptors (KD approximately 0.9 nM) and regulates feeding behavior. The N-terminal fragments (1-16), (1-16)NH2 are high affinity (KD approximately 6 nM) full agonists in vivo and in vitro. L-Ala substitutions show that amino acid residues Gly1, Trp2, Asn5, Tyr9, and Gly12 are important for the high affinity binding of galanin (1-16). Shortening the fragment (1-16) to galanin (1-7) causes a gradual drop of affinity: galanin (1-15), (1-14), and (1-13) have submicromolar KD values and galanin (1-12) has KD approximately 3 microM. Cyclic analogs of galanin (1-12) of different ring size were synthesized by condensing Gly1 and Gly12 without or with spacer groups. These analogs, independent of ring size, had a lower affinity than the linear galanin (1-12). Derivatization of the N-terminus of galanin (1-29), (1-16), and (1-12) all resulted in a large drop of affinity for the receptors, suggesting again the importance of the free N-terminal Gly. 相似文献
116.
A M Zharkovski? Iu L Langel K S Chereshka T A Zharkovskaia 《Biulleten' eksperimental'no? biologii i meditsiny》1987,103(3):317-319
In experiments on rats and mice the correlation between the ability of neuroleptics to antagonize apomorphine induced stereotypy and to block central dopamine and muscarinic acetylcholine receptors was studied. The analysis showed significant correlation (v = 0.76; P less than 0.05) between antistereotypic effects of drugs and their ability to inhibit 3H-spiperone binding to rat striated tissue. However, no correlation was found between antistereotypic effect of neuroleptics and their ability to block 3H-quinuclidinyl benzylate binding or arecoline-induced tremor. 相似文献