WO1999047566A1 - Peptides de synthese ameliorant la fixation de ldl - Google Patents

Peptides de synthese ameliorant la fixation de ldl Download PDF

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Publication number
WO1999047566A1
WO1999047566A1 PCT/US1999/005875 US9905875W WO9947566A1 WO 1999047566 A1 WO1999047566 A1 WO 1999047566A1 US 9905875 W US9905875 W US 9905875W WO 9947566 A1 WO9947566 A1 WO 9947566A1
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peptide
ldl
peptides
apolipoprotein
pharmaceutical composition
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PCT/US1999/005875
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English (en)
Inventor
Gattadahalli M. Anantharamaiah
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The Uab Research Foundation
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Priority to AU33568/99A priority Critical patent/AU3356899A/en
Publication of WO1999047566A1 publication Critical patent/WO1999047566A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to the field of cardiovascular medicine. More specifically, the present invention relates to synthetic peptides that enhance LDL uptake by cells.
  • Apolipoprotein E plays an important role in the metabolism of triglyceride-rich lipoproteins, such as very low
  • VLDL 1 density lipoprotein
  • chylomicrons Apolipoprotein E mediates the high affinity binding of apo E-containing lipoproteins to the low density lipoprotein (LDL) receptor (apo B, E receptor) and the members of its gene family, including LDL receptor related protein (LRP), very low density lipoprotein receptor (VLDLR) and the apoE2 receptor (apoE2R) (1).
  • LDL low density lipoprotein
  • LRP LDL receptor related protein
  • VLDLR very low density lipoprotein receptor
  • ApE2R apoE2 receptor
  • Apo E is secreted as a 299 amino acid residue protein with a molecular weight of 34,200.
  • a peptide LRKLRKRLLR-18A (hE-18A) is designed, in which LRKLRKRLLR (SEQ ID No. 1) is the 141 - 150 region of human apo E and 18A is a class A amphipathic helical peptide that associates with phospholipids and lipoprotein surfaces (17). To characterize the role of individual amino acid residues in the peptides several additional analogs were prepared. The receptor binding domain of apo E, LRKLRKRLLR, is well conserved in several species (Table 1). A peptide with the mouse apo E sequence, LRKMRKRLMR-18A (mE-18A, SEQ ID No.
  • Rat 133 LRKMRKRL R (SEQ ID No.7)
  • Bovine 140 LRKLPKRLLR (SEQ ID No.8)
  • Pig 140 LRNVRKRLVR (SEQ ID No.9) Dog 133 MRKLRKRVLR (SEQ ID No.10)
  • the italicized residues indicate changes from the human sequence, however, the property of the amino acid is conserved.
  • the bold- italicized residues indicate the difference in properties compared to the human sequence at that position.
  • the present invention is directed to the physical- chemical properties and the effects of these peptides on human
  • a synthetic apolipoprotein E-mimicking peptide comprising a receptor binding domain of apolipoprotein E covalently linked to a lipid-associating peptide.
  • th e lipid-associating peptide is model class A amphipathic helical peptide 18A.
  • the synthetic peptide is N-terminally protected using acetyl and amino groups.
  • the receptor binding domain of apolipoprotein E has an amino acid sequence selected from the group consisting of SEQ ID Nos. 1 - 3 and apolipoprotein E is from species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • the synthetic apolipoprotein E-mimicking peptide both enhances LDL binding to cells and increases LDL degradation by cells, e.g., by cells such as fibroblast cells.
  • a pharmaceutical composition comprising a synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • the present invention is further directed to applications of the pharmaceutical composition disclosed herein in enhancing LDL binding to a cell, increasing LDL degradation by a cell, lowering LDL cholesterol in an in-need individual or treating an individual with atherosclerosis by administering to the cell or individual with a pharmacologically effective dose of the pharmaceutical composition.
  • the effective dose is from about 0.01 mg/kg to about 100 mg/kg.
  • Figure 1 shows helical net analysis of the peptides 18A and hE18A.
  • the amino acids are shown in one letter code.
  • the hydrophobic residues are in dark circles and the charges of the amino acids are also shown.
  • Figure 2 shows agarose gel (0.7%) of LDL (10 ⁇ g)
  • LDL(10 ⁇ g) incubated with different concentrations of hE18A. The gel was stained with Coomassie Blue. Lanes: 1. LDL(10 ⁇ g), 2. LDL
  • Figure 3 A shows the effect of different concentrations of hE18A and Ac-hE18A-NH 2 on the specific internalization of 125 I-LDL in MEFl cells.
  • Cells were grown in DMEM in a monolayer in 6 well plates.
  • 125 I-LDL(10 ⁇ g) w as incubated with different concentrations of peptides (1 ⁇ g to 10 ⁇ g) at room temperature for 1 hour. This mixture was then incubated with the cells for 2 hours at 37°C and the effect of the peptide on internalization of LDL was measured after 2 hours incubation a t 37°C.
  • Figure 3B shows binding of 125 I-LDL to MEFl cells as a function of LDL concentration. Filled circles represent LDL without peptide and open circles represent LDL in presence of the peptide. The saturation in LDL binding that is observed in the absence of the peptide is abolished by the peptide.
  • Figure 4 shows internalization and degradation of 125 I-LDL(10 ⁇ g) in the presence of 10 ⁇ g Ac-hE18A-NH 2 , Ac- hE(R)18A-NH 2 , and Ac-mE18A-NH 2 .
  • the MEFl cells were grown and treated with I25 I-LDL-peptide and internalized was studied after a 2 hours incubation of cells at 37°C, while degradation w as measured after incubating cells for 5 hours at 37°C.
  • the black bars represent degradation and the grey bars represent internalization.
  • Figure 5 shows a comparison of the specific internalization of 125 I-LDL (10 ⁇ g) after coincubation with 10 ⁇ g of Ac-hE18A-NH2 for 1 hour at room temperature in wild type and LRP(-) /LRP(-) and LDL(-) mouse embryonic fibroblasts.
  • 125 I-LDL and peptide were coincubated for 1 h at room temperature and then filtered with a 0.22 ⁇ filter and incubated with the cells for 2 hours at 37°C.
  • the black bars represent wild type cells (MEFl)
  • the light grey bars represent LRP(-) cells
  • the dark grey b ars the LRP(-)/LDL(-) cells.
  • Figure 6 shows the effect of heparinase/heparitinase on the internalization of I25 I-LDL (10 ⁇ g) after incubating with Ac- hE 18A-NH 2 (10 ⁇ g) for 1 h at room temperature.
  • MEFl cells w ere pretreated with heparinase/heparitinase(3U/ml) for 2 hours a t 37°C and then incubated with 125 I-LDL-peptide for 2 hours a t 37°C.
  • the black bars represent internalization without heparinase/heparitinase treatment while the grey bars represent internalization after pretreatment with heparinase/heparitinase.
  • apo E Human apolipoprotein E consists of two distinct domains, the lipid-associating domain (residues 192-299) and th e globular domain (1-191) which contains the LDL receptor binding site (residues 129-169).
  • lipid-associating domain lipid-associating domain
  • th e globular domain (1-191) which contains the LDL receptor binding site
  • LDL low density lipoprotein
  • LDL internalization was enhanced three, five and seven times by Ac- mE18A-NH 2 , Ac-hE18A-NH 2 , and Ac-hE(R)18A-NH 2 respectively. All three peptides increased degradation of LDL by 100 percent. The LDL binding to fibroblasts in the presence of these peptides was not saturable, however, over the LDL concentration range studied. Furthermore, a similar enhancement of LDL internalization was observed independent of the presence of the LDL receptor related protein (LRP) or LDL receptor or both.
  • LRP LDL receptor related protein
  • 1 1 directed the LDL-peptide complex to the HSPG pathway for uptake and degradation by fibroblasts.
  • a synthetic apolipoprotein E-mimicking peptide comprising a receptor binding domain of apolipoprotein E covalently linked to a lipid-associating peptide.
  • the lipid-associating peptide is model class A amphipathic helical peptide 18 A.
  • the synthetic peptide is N- terminally protected using acetyl and amino group.
  • the present invention is directed to the receptor binding domain of apolipoprotein E has a n amino acid sequence selected from the group consisting of SEQ ID Nos. 1-3 and apolipoprotein E is from species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • the present invention is directed to a synthetic apolipoprotein E-mimicking peptide th at both enhances LDL binding to cells and increases LDL degradation by cells.
  • the present invention is directed a pharmaceutical composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • the present invention is further directed to applications of the pharmaceutical composition disclosed herein in enhancing LDL binding to a cell, increasing LDL degradation by a cell, lowering LDL cholesterol in an in-need individual or treating an individual with atherosclerosis by administering to the cell or individual with a pharmacologically effective dose of th e
  • the effective dose is from about 0.01 mg/kg to about 100 mg/kg.
  • Peptides were synthesized using the solid phase method and Fmoc chemistry, and a peptide synthesizer from Protein Technology, according to the procedure described previously (19).
  • the peptide resin was subjected to HF cleavage to ensure the complete removal of the 4-methoxy-2,3 ,6- trimethylbenzenesulfonyl (Mtr) group from Arg residues.
  • Trp, mercaptoethanol and dimethyl sulfide were used as scavengers and for the cleavage of mE-18A, Met, Trp, mercaptoethanol and dimethylsulfide w ere used as scavengers.
  • the cleaved peptides were purified on a preparative C-4 re versed-phase HPLC column and purity w as determined by C-18 analytical reversed phase HPLC and confirmed by mass spectral analysis.
  • Plasma LDL was prepared by sequential density ultracentrifugation (20) using human plasma obtained from th e
  • VLDL 1 3 Red Cross.
  • VLDL was removed by centrifuging plasma (density of 1.006 g/ml) at 50000 rpm in a 50Ti Sorvall rotor for 18 h.
  • the density of the VLDL deficient plasma was adjusted to 1.063 g/ml with potassium bromide and centrifuged at 50000 rpm to obtain LDL.
  • the LDL (1.006-1.063 g/ml) was washed with 150 mM NaCl by overlayering and recentrifuging and dialyzed exhaustively against 150 mM NaCl containing 0.24mM EDTA.
  • LDL fraction Purity of the LDL fraction was determined by Superose 6 (Pharmacia, Inc) column chromatography and by agarose electrophoresis.
  • the density of plasma was adjusted to 1.21 g/ml with potassium bromide and centrifuged at 50,000 rpm at 4°C for 24 h.
  • the top fraction consisting of lipoproteins was removed.
  • the lower fraction, which is devoid of lipoproteins, was dialyzed extensively against 150 mM NaCl at 4°C for 60 h.
  • the LPDS w sterilized by filtration through a 0.22 ⁇ m Millipore filter.
  • Agarose gel elctrophoresis was carried out according to the procedure of Asztalos (22). LDL and the LDL-peptide mixture were electrophoresed on a 0.7% agarose gel. Tris-tricine buffer (25 mM, pH 8.6) was used for both gel and electrode buffers. Since the peptides are positively charged, the wells were made in the center of the gel to allow for movement in both directions. 2 ⁇ l samples (containing about 5 ⁇ g of LDL) were diluted with 2 ⁇ l of Tris-tricine buffer containing 10% glycerol and bromophenol blue. Samples were eletrophoresed at a constant voltage of 250 volts for about 2 h or until the dye reached the top of the gel.
  • the gel was stained with Coomassie blue.
  • 125 I-labeled peptides w ere used and the stained bands were excised and counted to determine the ratio of peptide to LDL.
  • the cells After washing with ice cold PBS (containing BSA 2 mg/ml), to remove excess free labeled lipoprotein, the cells were incubated with dextran sulfate (4 mg/ml, Pharmacia, M r 500,000) or heparin (Sigma Chemical Co., 10 mg/ml) for 1 h to release spcifically bound 125 I-LDL., and washed with cold PBS.
  • dextran sulfate 4 mg/ml, Pharmacia, M r 500,000
  • heparin Sigma Chemical Co., 10 mg/ml
  • the cells were dissolved in 0.1 N NaOH and a 0.5 m l aliquot of cell suspension was counted. These counts reflect the amount of LDL internalized. Protein was estimated by the method of Lowry. Degradation of LDL were studied using the protocol described above for 4°C, except that the cells were incubated a t 37°C for 5 hours. Degradation was determined by precipitating the unbound 125 I-LDL from the medium with 50% TCA ( 0.5 ml of 50% TCA was added to 1 ml of medium) and incubating at 4°C for 30 minutes (20). The precipitate was removed by centrifugation. The supernatant was treated with 10 ⁇ l of 40% potassium iodide and 40 ⁇ l of 30% hydrogen peroxide.
  • Heparinase and heparitinase treatment of cells w as carried out as follows. The cells were treated with heparinase and
  • CD spectra were recorded on a signal averaging AVIV 62DS spectropolarimeter as described earlier (18). Briefly, CD spectra were obtained at 25°C by signal averaging of four scans recorded every nm from 260 nm to 190 nm using a cell with a 0.01 cm path length Peptide concentrations in PBS, pH 7.4, u s ed were 100 ⁇ M. Peptide-DMPC complexes (1 :20 m/m) w ere prepared as described (18) and the change in peptide helicity upon lipid association measured.
  • the helical content of the peptides was estimated from the mean residue ellipticity, [ ⁇ ] MRE (deg.cm 2 .dmol 1 ) at 222 nm using the equations as detailed b y Morrisett et al.(23).
  • hE18A has a localized net positive charge (arginine and lysine rich) that can bind to negative charges and a hydrophobic strip that can bind to lipids.
  • An increase in helicity of the peptides would increase the localization of the positive charges that would enhance the ability of th e peptide to bind to negatively charged molecules.
  • LDL LDL can be seen as a single, homogenous band migrating toward the anode (lane 1) while th e peptide (10 ⁇ g) appeared as a diffuse band migrating toward th e cathode (lane 6).
  • the anodic mobility of the LDL treated with peptide was retarded and the degree of retardation of mobility
  • the peptides were designed to mimic apo E, containing the minimal LDL receptor binding domain as well as a lipid binding domain. These peptides were used to determine this potential impact on receptor mediated binding and uptake of LDL in mouse fibroblasts.
  • concentrations (1-10 ⁇ g) of th e petides, hE18A and Ac-hE18A-NH 2 with LDL constant at 10 ⁇ g ( Figure 3A) specific internalization of LDL was dependent on th e concentration of peptide used.
  • Ac-hE18A-NH 2 was 5 times more effective than with hE18A. This was also true for the other analogs.
  • th e control peptide Ac- 18A-NH 2 and the receptor binding region b y
  • the effect of the peptide was studied in two ways: (a) the peptide was added to the cell media directly after adding LDL and (b) it was first incubated with LDL for 1 h at room temperature and the coincubated mixture was added to the cells after filtering through a 0.22 ⁇ filter.
  • the peptide-LDL "complex" or modified LDL appears to enhance the uptake of 125 I-LDL much more than the peptide by itself (results not shown).
  • the peptides also enhance degradation of LDL in these cells (Figure 4). Even though they enhance internalization of LDL to different amounts, they all enhance the degradation of LDL to the same extent, approximately 2-fold. It is possible that th e degradation reflects the LDL being internalized through the receptor dependent pathway but this is not so since ligand blots showed that the peptide-LDL complex does not bind to the LDL receptor (results not shown). ApoE mediates the uptake of lipoproteins through the
  • LRP-/- LRP deficient cells
  • LDL-/- and LRP- /- LDL and LRP deficient cells
  • Heparan sulfate proteoglycans bind and take up apo E- enriched lipoproteins (27).
  • the receptor binding domain of apoE has been shown to coincide with the heparin binding domain (28).
  • These apo E mimicking peptides could modify LDL and be taken up through heparan sulfate proteoglycans. Therefore, the cells were treated with heparinase and heparitinase (0.5 units each/ml).
  • Nikoulin and Curtis (13) have shown that a modified dimer of the receptor binding domain binds to LDL and increases LDL binding to fibroblasts. The increase in the the peptide- mediated uptake of these peptides appears to be via the LRP and the HSPG pathway. However, it is not clear whether this N- acetylated dimer peptide increases degradation of LDL.
  • Comparison of peptide:LDL stoichiometry obtained by the dimer peptides of Nikoulin and Curtis (13) (5 molecules of peptide p er LDL) and the E-18A peptides reported in this study (30 molecules of peptide per LDL) indicate enhanced binding of the E- 18A peptides to LDL surface. This could be due to the presence of the lipid binding domain, 18A. This increased binding could b e responsible for the enhanced degradation that was observed.
  • the anionic peptide used by Braddock et al. (15) also bound LDL and increased LDL binding by 6-7 times, in LDL receptor negative fibroblasts. However, degradation was only 10% of that in LDL receptor positive cells. Moreover, this peptide w as active in both LRP/LDL deficient cells as well as in cells treated with heparinase, implicating a pathway different from the ones observed by the peptides of LDL described herein.
  • lipid binding region therefore appears to be playing a maj or role in internalization.
  • Apo E binds preferentially to larger lipoproteins. It is suggested that by changing the lipid binding domain (the hydrophobic nature and or the length) of these apo E mimetic peptides, peptides could be designed to target other lipoproteins and effect a greater internalization of these.
  • the present invention demonstrates that if the apo E-receptor binding domain, which is also a receptor binding domain, is able to associate strongly with LDL, this is sufficient to increase the LDL binding to cells.
  • These peptides are able to enhance both internalization and degradation. This enhancement appears to be through the heparan sulfate proteoglycans pathway. Since LDL degradation is correlated to decreased LDL plasma cholesterol, these studies thus open th e possibility of decreasing plasma LDL with these peptides.
  • transgenic mouse model can be produced for a model synthetic peptide (30), it will be interesting to express this peptide in an apo E knockout mouse model and study the effect of the expressed peptide on spontaneously-developed atherosclerosis that is seen in apoE knock out mice (4). These studies are therefore important in designing apo E-mimicking peptides that can be easily synthesized and potentially be used for therapeutic intervention of atherosclerosis.

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Abstract

La présente invention concerne de nouveaux peptides de synthèse imitant l'apolipoprotéine E (ApoE), dans lesquels le domaine de liaison du récepteur de l'apolipoprotéine E est lié par covalence à 18A, peptide modèle hélicoïdal amphipathique de classe A, d'association lipidique, bien caractérisé. De tels peptides améliorent la fixation de lipoprotéines de basse densité (LDL) à des cellules de fibroblastes ou de HepG2, ainsi que leur dégradation par ces cellules. L'invention concerne également des applications possibles de ces peptides de synthèse dans la réduction du taux de cholestérol LDL du plasma humain, inhibant ainsi l'athérosclérose.
PCT/US1999/005875 1998-03-17 1999-03-17 Peptides de synthese ameliorant la fixation de ldl WO1999047566A1 (fr)

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Cited By (13)

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US6664230B1 (en) 2000-08-24 2003-12-16 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US6930085B2 (en) 2002-04-05 2005-08-16 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
US7144862B2 (en) 2000-08-24 2006-12-05 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7148197B2 (en) 2000-08-24 2006-12-12 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US7166578B2 (en) 2000-08-24 2007-01-23 The Regents Of The University Of California Orally administered peptides synergize statin activity
US7199102B2 (en) 2000-08-24 2007-04-03 The Regents Of The University Of California Orally administered peptides synergize statin activity
US7250304B2 (en) 2000-03-31 2007-07-31 The Regents Of The University Of California Functional assay of high-density lipoprotein
WO2009032693A2 (fr) 2007-08-28 2009-03-12 Uab Research Foundation Polypeptides de synthèse imitant l'apolipoprotéine e et leurs procédés d'utilisation
FR2937322A1 (fr) * 2008-10-22 2010-04-23 Vect Horus Derives peptidiques et leur utilisation comme vecteurs de molecules sous forme de conjugues
US20120245101A1 (en) * 2007-08-28 2012-09-27 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
US8877716B2 (en) 2010-04-21 2014-11-04 Vect-Horus Peptide derivatives, preparation and uses thereof
US10653747B2 (en) 2014-07-31 2020-05-19 Uab Research Foundation ApoE mimetic peptides and higher potency to clear plasma cholesterol
CN114569720A (zh) * 2022-02-21 2022-06-03 中国科学院动物研究所 抑制apoe蛋白活性和/或表达量的物质在延缓衰老中的应用

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Cited By (29)

* Cited by examiner, † Cited by third party
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US7250304B2 (en) 2000-03-31 2007-07-31 The Regents Of The University Of California Functional assay of high-density lipoprotein
US6933279B2 (en) 2000-08-24 2005-08-23 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7144862B2 (en) 2000-08-24 2006-12-05 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7148197B2 (en) 2000-08-24 2006-12-12 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US7166578B2 (en) 2000-08-24 2007-01-23 The Regents Of The University Of California Orally administered peptides synergize statin activity
US7199102B2 (en) 2000-08-24 2007-04-03 The Regents Of The University Of California Orally administered peptides synergize statin activity
US6664230B1 (en) 2000-08-24 2003-12-16 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7638494B2 (en) 2002-04-05 2009-12-29 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
US6930085B2 (en) 2002-04-05 2005-08-16 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
EP2195331A4 (fr) * 2007-08-28 2011-05-11 Uab Research Foundation Polypeptides de synthèse imitant l'apolipoprotéine e et leurs procédés d'utilisation
US20120245101A1 (en) * 2007-08-28 2012-09-27 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
US9422363B2 (en) * 2007-08-28 2016-08-23 Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
EP2195331A2 (fr) * 2007-08-28 2010-06-16 UAB Research Foundation Polypeptides de synthèse imitant l'apolipoprotéine e et leurs procédés d'utilisation
US20100298215A1 (en) * 2007-08-28 2010-11-25 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
WO2009032693A2 (fr) 2007-08-28 2009-03-12 Uab Research Foundation Polypeptides de synthèse imitant l'apolipoprotéine e et leurs procédés d'utilisation
AU2008296478B2 (en) * 2007-08-28 2014-08-28 The Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
US8729029B2 (en) 2008-10-22 2014-05-20 Vect-Horus Peptide derivatives and use thereof as carriers for molecules in the form of conjugates
JP2012506407A (ja) * 2008-10-22 2012-03-15 ヴェクト−オリュス ペプチド誘導体、およびコンジュゲートの形態での分子用ベクターとしてのそれらの使用
FR2937322A1 (fr) * 2008-10-22 2010-04-23 Vect Horus Derives peptidiques et leur utilisation comme vecteurs de molecules sous forme de conjugues
CN102282159A (zh) * 2008-10-22 2011-12-14 维克塔-霍洛斯公司 肽衍生物及其以结合物形式作为分子载体的应用
CN102282159B (zh) * 2008-10-22 2015-11-25 维克塔-霍洛斯公司 肽衍生物及其以结合物形式作为分子载体的应用
JP2015212264A (ja) * 2008-10-22 2015-11-26 ヴェクト−オリュスＶｅｃｔ−Ｈｏｒｕｓ ペプチド誘導体、およびコンジュゲートの形態での分子用ベクターとしてのそれらの使用
EA022976B1 (ru) * 2008-10-22 2016-04-29 Вект-Орюс Пептидные производные и их применение в качестве векторов молекул в форме конъюгатов
US9328143B2 (en) 2008-10-22 2016-05-03 Vect-Horus Peptide derivatives and use thereof as carriers for molecules in the form of conjugates
WO2010046588A1 (fr) * 2008-10-22 2010-04-29 Vect-Horus Derives peptidiques et leur utilisation comme vecteurs de molecules sous forme de conjugues
US8877716B2 (en) 2010-04-21 2014-11-04 Vect-Horus Peptide derivatives, preparation and uses thereof
US10653747B2 (en) 2014-07-31 2020-05-19 Uab Research Foundation ApoE mimetic peptides and higher potency to clear plasma cholesterol
CN114569720A (zh) * 2022-02-21 2022-06-03 中国科学院动物研究所 抑制apoe蛋白活性和/或表达量的物质在延缓衰老中的应用
CN114569720B (zh) * 2022-02-21 2023-06-09 中国科学院动物研究所 抑制apoe蛋白活性和/或表达量的物质在延缓衰老中的应用

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