WO1999064449A2 - Cell-permeable peptide - Google Patents
Cell-permeable peptide Download PDFInfo
- Publication number
- WO1999064449A2 WO1999064449A2 PCT/GB1999/001848 GB9901848W WO9964449A2 WO 1999064449 A2 WO1999064449 A2 WO 1999064449A2 GB 9901848 W GB9901848 W GB 9901848W WO 9964449 A2 WO9964449 A2 WO 9964449A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptide
- positively charged
- cell permeable
- signal peptide
- cell
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
- C07K14/003—Peptide-nucleic acids (PNAs)
-
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/50—Fibroblast growth factors [FGF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
- C12N15/625—DNA sequences coding for fusion proteins containing a sequence coding for a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/60—Fusion polypeptide containing spectroscopic/fluorescent detection, e.g. green fluorescent protein [GFP]
Definitions
- the present invention relates to the delivery of molecules into a cell and the use of modified signal peptides.
- a modified analogue of the signal peptide sequence from Karposi syndrome fibroblast growth factor (kFGF) is used as a cell-permeant vehicle for the intracellular delivery of covalently linked anti-sense peptide nucleic acid sequences (PNAs) .
- PNAs covalently linked anti-sense peptide nucleic acid sequences
- PNAs have potential uses as antisense molecules for the control of gene expression. Since they are capable of binding tightly to DNA and RNA targets thus preventing DNA transcription to RNA and RNA translation to protein. These molecules thus have two potential uses of commercial importance:
- a signal peptide is a short-lived _V-terminal sequence found only on nascent proteins which are synthesised m the endoplasmic reticulum.
- Signal peptides consist of three domains:
- Synthetic peptides consisting of only the hydrophobic cores are typically insoluble m water.
- the signal peptide sequence of Karposi syndrome-derived FGF as an example, we have modified these insoluble sequences by the addition of positively charged ammo acids (for example lysmes) , which have the effect of rendering them water soluble without compromising their ability to translocate across cellular membranes.
- ammo acids for example lysmes
- a cell permeable peptide comprising at least the hydrophobic core of a signal peptide or an analogue thereof wherein the peptide is modified by the addition of at least one positively charged amino acids or positively charged analogues thereof .
- the signal peptide may be a natural or synthetic signal peptide or a peptide which is substantially similar thereto.
- a peptide which is substantially similar to a signal peptide is at least 60% homologous thereto.
- At least one positively charged amino acid is chosen from lysine and/or arginine and/or any positively charged analogues thereof.
- the cell permeable peptide is a modified analogue of Karposi syndrome fibroblast growth factor (kFGF) .
- kFGF Karposi syndrome fibroblast growth factor
- the positively charged amino acid consists of one or more lysine residues.
- the invention further provides the use of cell permeable peptides as described herein for intracellular delivery of a molecule.
- one or more lysine residues will be attached to the C terminal of the signal sequence peptide or signal sequence peptide analogue.
- This positively charged lysine allows the linkage of a peptide nucleic acid, thus facilitating m vivo delivery of the said peptide nucleic acid.
- the invention also provides a cell permeable peptide which contains multiple positively charged ammo acids or positively charged analogues thereof wherein a peptide nucleic acid may be conjugated to each positively charged residue and wherein the peptide nucleic acids conjugated by such a means are identical or different.
- the invention also provides a cell permeable peptide which comprises at least one positively charged ammo acid residue or functionally equivalent positively charged analogue thereof conjugated or conjugatable to a lysine tree, to which multiple peptide nucleic acids may be joined for transport and presentation.
- the linked peptide nucleic acid sequence may be antisense.
- the peptide nucleic acid sequence will be covalently linked.
- the present invention thus allows the use of cell permeable peptides as described herein to deliver peptide nucleic acids to ln-vivo targets.
- PNAs Polymethyl methacrylate-N-(2-ammoethyl)-N-(2-ammoethyl) glycme units to which natural nucleobases are attached through methylenecarbonyl linkers.
- N- (2-ammoethyl) glycme units to which natural nucleobases are attached through methylenecarbonyl linkers.
- PNAs suffer from similar accessibility problems as phosphorothioates do, and passive diffusion of unmodified PNA across lipid membranes is not efficient ( ittung, P., et al . , 1995) .
- a small number of native peptide sequences can translocate across membranes of living cells in an energy- independent and receptor- independent manner. These peptides have been used to import active cargo into the cell. For example a peptide from the homeodomain of Antennapedia has been successfully used to import both peptidal inhibitors of protein kinase C (Theodore, et al . , 1995) and conventional anti-sense oligonucleotides (Allinquant, et al . , 1995) .
- the present invention provides use of cell permeable peptide import (CPPI) to deliver peptide nucleic acids (PNAs) .
- CPPI cell permeable peptide import
- PNAs peptide nucleic acids
- the present invention provides use of the signal peptide sequence from Karposi syndrome fibroblast growth factor (kFGF) for delivery of antisense peptide nucleic acid sequences (PNAs) .
- kFGF Karposi syndrome fibroblast growth factor
- PNAs antisense peptide nucleic acid sequences
- the invention provides use of a peptide as defined herein together with lysine residues for multiple presentation of peptide nucleic acids.
- the invention further provides use of peptides as defined herein together with lysine residues in the simultaneous presentation of different peptides nucleic acids.
- the present invention combines the two above technologies to use CPPI to deliver PNAs to in vi vo targets .
- the modified signal peptides described m this invention can be used for the delivery of any cell-impermeant substance into cells.
- the signal peptides described m this invention can be used to improve the delivery of substances of low permeability into cells.
- the signal peptide delivery system has commercial value m therapeutic drug-delivery systems including, but not restricted to, gene therapy, cancer therapy and anti-mfectious agent therapy.
- This system also has commercial value as a tool for biochemical and molecular biological research.
- Figure 1 illustrates carboxyfluorescein labelled kFGF signal peptide-Lys .Lys .Lys - fluoresence calibration curve .
- Figure 2 illustrates carboxfluorescein labelled cell permeant peptide incorporation by whole human endothelial cells.
- Figure 3 depicts incorporation of carboxyfluorescein labelled signal peptide-Lys . Lys . Lys by cell.
- Figure 4 illustrates subcellular distribution of labelled signal peptide in cells.
- Figure 5 depicts incorporation of labelled kFGF peptide into human dermal endothelial cells.
- Figure 6a sets out the signal peptide sequence and modifications.
- Figure 6b illustrates simultaneous presentation of 3 PNAs directed to different sites on a target RNA.
- Figure 6c illustrates multiple presentation of the single PNA species.
- Table 1 describes carboxyfluorescein derivatised cell permeant peptides.
- Table 2a sets out uptake of cell permeant peptides by cells.
- Table 2b sets out cellular uptake of permeant peptides by BHK cells.
- Table 3 sets out results of washing labelled antennapedia cells.
- Table 4 sets out washing results for labelled signal peptide-KKK and cells.
- the raw relative fluorescent units (RFU) values were converted to nMoles per 10 6 cells using a calibration curve constructed for each peptide.
- An example of a fluorescence calibration curve of fluorescein labelled kFGF is shown in Figure 1.
- the kFGF-KKK sequence shows similar high rates of cytosolic and nuclear incorporation compared with the antennapedia peptide (Table 2A) .
- the PKC and substance P peptides show much lower incorporation Table 2A & 2B) .
- Incorporation of the kFGF-KKK sequence is saturable, as can be seen from the data presented on Figure 2 and time-dependent as shown in Figure 3.
- Table 2A shows that antennapedia is lost during subcellular fractionation. Unlike the antennapedia peptide, carboxyfluorescein-kFGF signal peptide-KKK is not loosely attached to the cell surface as shown in Tables 3 and 4. Unlike the antennapedia peptide, carboxyfluorescein-kFGF signal peptide-KKK does not remain membrane -bound as shown by the data presented in Figure 4.
- oligonucleotide sequences or those in which the phosphodiester bonds are replaced with nuclease-resistant bonds may be conjugated to the kFGF-derived delivery system for intracellular delivery and subsequent specific blocking of gene translation or Rnase-targeted destruction of the mRNA in question.
- nuclease-resistant bonds such as the phosphothiorates and the like
- peptide nucleic acid sequences may be used, as m example 1.
- PNA Peptide Nucleic Acid
- Nuclear localisation signal (NLS) sequences such as are found on transcription factors like NF-kappaB may be conjugated to the kFGF-derived delivery system, as m Example 1. Intracellular delivery of NLS peptide sequences would act as 'bait' to selectively block the translocation of the selected transcription factor, thus preventing its action. In this way, genes under the control of the transcription factor could be identified on the basis of down regulated expression.
- NLS Nuclear localisation signal
- Signal transduction motifs such as phosphotyros e- containing peptide sequences (pYP's) act as docking sites for a large number of proteins.
- Such signalling proteins contain domains that recognise (contextually) the phosphotyrosme residues and bind to them m a specific manner.
- pYP's are recognised by SH-2 (Src- homology-2) domains and PTB (phosphotyrosme binding domains) .
- Specificity is provided by short ammo acid sequences iV-and/or C-termmal of the phosphotyrosme.
- Such peptide motifs could be conjugated to the kFGF peptide-de ⁇ ved delivery system as m Example 1, and could be used to mtracellularly deliver pYP's which would act as bait, thus allowing signal pathways to be 'interrogated'.
- FIG. 6A The signal sequence of kFGF was modified to contain three lysmes at the C-termmal of the hydrophobic signal sequence. This procedure is illustrated m Figure 6A.
- Figure 6A (I) shows the signal peptide with an attached reporter group.
- Figure 6A Part II illustrates the addition of the t ⁇ -lysme extension to the C-termmal of the signal peptide sequence, thus providing three positive charges which aid solubility and cell permeability.
- Figure 6A Part Illb the peptide nucleic acid forms part of the linear primary ammo acid sequence, with Part IV illustrating a t ⁇ -lysme C-termmal extension to the peptide nucleic acid sequence providing 3 positive charges and aiding solubility and cell permeability.
- Part V of Figure 6A further shows a tri-lysyl extension at the N-termmal of the signal peptide which provides 3 positive charges aiding solubility and cell permeability.
- the addition of the tri-lysyl extension proximal to the carboxyfluorescein reporter group enhances its fluorescence.
- the peptide nucleic acid sequence initially forms part of the linear primary ammo acid sequence at the N- terminal of the original peptide, before a tri-lysyl extension is added to the N-termmal of the peptide nucleic acid extension.
- This peptide therefore, can accommodate three PNAs, each bonded to a lysine epsilon amino group.
- This can be extended using the Multiple Antigen Presentation (MAP) technology to present eight (or more) PNA' s on one kFGF signal sequence.
- MAP Multiple Antigen Presentation
- a 'lysine tree' constructed in this way accommodates eight copies of the same PNA, thus increasing the effective concentration delivered by each CPPI.
- Part I An example of the addition of such a lysine tree is shown in Figure 6C Parts I -IV.
- Part I a single lysine molecule added to the C-terminal of the kFGF signal peptide sequence allows the multiple PNA lysine tree to be added to the e-amino group of the lysine side chain.
- a lysine molecule added to the N-terminal of the kFGF signal peptide sequence allows the multiple PNA lysine tree to be added to the e-amino group of the lysine side chain.
- Part III of Figure 6C further shows that when a C- terminal tri-lysine extension is added to the signal peptide with N-terminal associated multiple PNA lysine tree, the 3 positive charges aid solubility and cell permeability of the molecule.
- Part IV of Figure 6C add a tri-lysyl extension at the N-terminal of the signal peptide which is attached to the lysine group added to allow attachment of the multiple PNA lysine tree as originally illustrated in Figure 6C Part II.
- the addition of the 3 positively charged molecules at this terminal of the molecule, proximal to the carboxyfluorescein reporter group enhances its fluorescence.
- a carrier can be constructed containing three (or more) different PNAs directed towards different sites on the same target mRNA. This strategy has been termed 'molecular triangulation' (Branch, A.D. , 1998) .
- Figure 6B illustrates this process of 'molecular triangulation' .
- Figure 6B Part I shows the signal peptide with a C-terminal tri-lysyl extension which allows three different PNA sequences to be conjugated to the epsilon-amino groups of the three lysines.
- Figure 6B Part III shows the addition of a further three lysines to the molecule of Part I, which adds three positive charges, which aid solubility and cell permeability.
- Figure 6B Part III shows the addition of the tri-lysyl extension to the N-terminal of the molecule of Part I. Again the 3 positive charges aid the solubility and cell permeability of the molecule, which their proximal location to the carboxyfluorescein reporter group enhances its fluorescence.
- Figure 6B Part IV, illustrates an N-terminal tri-lysyl extension added to the kFGF signal peptide sequence, which subsequently allows three different PNA sequences to be conjugated to the epsilon-amino groups of the lysines. Further, this molecule has 3 lysines added at the C- terminal to add positive charge which aid solubility and cell permeability.
- Figure 6B Part V shows the signal peptide again with the three peptide nucleic acid associated tri-lysine extension at the N-terminal, but with the addition of the further 3 lysine groups also being made to the N-terminal where they will have the effect of aiding solubility and cell permeability, which also enhance the fluorescence of the carboxyfluorescein reporter group due to their proximity.
- Lysine extensions comprising more or less than three lysine residues may also be useful to provide additional solubility and cell permeability.
- the lysine extension may be provided next to a carboxyfluorescein reporter group to enhance its fluorescence.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99955476A EP1086126A1 (en) | 1998-06-10 | 1999-06-10 | Cell-permeable peptide |
AU42819/99A AU4281999A (en) | 1998-06-10 | 1999-06-10 | Peptide |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9812376.3 | 1998-06-10 | ||
GBGB9812376.3A GB9812376D0 (en) | 1998-06-10 | 1998-06-10 | |
GB9814888.5 | 1998-07-10 | ||
GBGB9814888.5A GB9814888D0 (en) | 1998-07-10 | 1998-07-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1999064449A2 true WO1999064449A2 (en) | 1999-12-16 |
WO1999064449A3 WO1999064449A3 (en) | 2002-10-24 |
Family
ID=26313825
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/001848 WO1999064449A2 (en) | 1998-06-10 | 1999-06-10 | Cell-permeable peptide |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1086126A1 (en) |
AU (1) | AU4281999A (en) |
WO (1) | WO1999064449A2 (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001027154A2 (en) * | 1999-09-27 | 2001-04-19 | Mahony Daniel J O | Membrane translocating peptide drug delivery system |
WO2001057072A2 (en) * | 2000-02-07 | 2001-08-09 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of their use |
WO2002055545A1 (en) * | 2001-01-12 | 2002-07-18 | Rhobio | Antimicrobial pseudopeptides |
EP1339431A1 (en) * | 2000-11-30 | 2003-09-03 | Unigene Laboratories, Inc. | Improved oral delivery of peptides using enzyme-cleavable membrane translocators |
GB2346616B (en) * | 1998-11-13 | 2004-04-21 | Cyclacel Ltd | Transport vectors |
EP1862471A2 (en) * | 2000-02-07 | 2007-12-05 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of their use |
US7316819B2 (en) | 2001-03-08 | 2008-01-08 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
US7432045B2 (en) | 2003-12-01 | 2008-10-07 | Wisconsin Alumni Research Foundation | Method of inhibiting influenza infection with antiviral peptides |
US8017727B2 (en) | 1999-09-27 | 2011-09-13 | Merrion Research Iii Limited | Conjugates of membrane translocating agents and pharmaceutically active agents |
US8088734B2 (en) | 2003-01-21 | 2012-01-03 | Unigene Laboratories Inc. | Oral delivery of peptides |
US8835377B2 (en) | 2004-06-18 | 2014-09-16 | Ugp Therapeutics, Inc. | Oral delivery of peptide pharmaceutical compositions |
US20150119340A1 (en) * | 2013-10-29 | 2015-04-30 | Samsung Electronics Co., Ltd. | Fusion peptide and use thereof for cell membrane penetrating |
US10072065B2 (en) | 2015-08-24 | 2018-09-11 | Mayo Foundation For Medical Education And Research | Peptide-mediated delivery of immunoglobulins across the blood-brain barrier |
US10377813B2 (en) | 2009-07-14 | 2019-08-13 | Mayo Foundation For Medical Education And Research | Peptide-mediated non-covalent delivery of active agents across the blood-brain barrier |
US10421967B2 (en) | 2014-05-15 | 2019-09-24 | Hoffmann-La Roche Inc. | Oligomers and oligomer conjugates |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997004006A1 (en) * | 1995-07-18 | 1997-02-06 | Friedhelm Herrmann | Substance for use against tumour growth and viral infections |
-
1999
- 1999-06-10 EP EP99955476A patent/EP1086126A1/en not_active Withdrawn
- 1999-06-10 AU AU42819/99A patent/AU4281999A/en not_active Abandoned
- 1999-06-10 WO PCT/GB1999/001848 patent/WO1999064449A2/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997004006A1 (en) * | 1995-07-18 | 1997-02-06 | Friedhelm Herrmann | Substance for use against tumour growth and viral infections |
Non-Patent Citations (5)
Title |
---|
ALLINQUANT B ET AL., : "Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro" THE JOURNAL OF CELL BIOLOGY, vol. 128, no. 5, March 1995 (1995-03), pages 919-927, XP000856389 cited in the application * |
DU C ET AL., : "Conformational and topological requirements of cell-permeable peptide function" JOURNAL OF PEPTIDE RESEARCH, vol. 51 (3), March 1998 (1998-03), page 235-243 XP000856550 * |
FULLER-PACE F ET AL., : "Cell transformation by kappaFGF requires secretion but not glycosylation" J. CELL. BIOL. , vol. 115, no. 2, 1991, pages 547-555, XP000856406 * |
LIN Y-Z ET AL., : "Inhibition of nuclear translocation of transcription factor NF-kappaB by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence" JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 24, 1995, pages 14255-14258, XP002050723 * |
ROJAS M. ET AL., : "Controlling epidermal growth factor (EGF)-stimulated Ras activation in intact cells by a cell-permeable peptide mimicking phosphorylated EGF receptor" JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 271, no. 44, 1996, page 27456-27461 XP002124151 * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2346616B (en) * | 1998-11-13 | 2004-04-21 | Cyclacel Ltd | Transport vectors |
US8017727B2 (en) | 1999-09-27 | 2011-09-13 | Merrion Research Iii Limited | Conjugates of membrane translocating agents and pharmaceutically active agents |
WO2001027154A3 (en) * | 1999-09-27 | 2002-06-20 | Daniel J O'mahony | Membrane translocating peptide drug delivery system |
WO2001027154A2 (en) * | 1999-09-27 | 2001-04-19 | Mahony Daniel J O | Membrane translocating peptide drug delivery system |
US7371809B2 (en) | 2000-02-07 | 2008-05-13 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides |
WO2001057072A2 (en) * | 2000-02-07 | 2001-08-09 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of their use |
JP2003522185A (en) * | 2000-02-07 | 2003-07-22 | ウイスコンシン アラムニ リサーチ ファンデーション | Pharmacologically active antiviral peptides and their use |
US8748565B2 (en) | 2000-02-07 | 2014-06-10 | Wisconsin Alumni Reseach Foundation | Pharmacologically active antiviral peptides and methods of their use |
EP1862471A2 (en) * | 2000-02-07 | 2007-12-05 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of their use |
JP4896333B2 (en) * | 2000-02-07 | 2012-03-14 | ウイスコンシン アラムニ リサーチ ファンデーション | Pharmacologically active antiviral peptides and methods of use thereof |
US8748566B2 (en) | 2000-02-07 | 2014-06-10 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of use |
EP1862471A3 (en) * | 2000-02-07 | 2008-05-28 | Wisconsin Alumni Research Foundation | Pharmacologically active antiviral peptides and methods of their use |
WO2001057072A3 (en) * | 2000-02-07 | 2002-10-31 | Wisconsin Alumni Res Found | Pharmacologically active antiviral peptides and methods of their use |
EP1339431A1 (en) * | 2000-11-30 | 2003-09-03 | Unigene Laboratories, Inc. | Improved oral delivery of peptides using enzyme-cleavable membrane translocators |
EP1339431A4 (en) * | 2000-11-30 | 2005-10-12 | Unigene Lab Inc | Improved oral delivery of peptides using enzyme-cleavable membrane translocators |
WO2002055545A1 (en) * | 2001-01-12 | 2002-07-18 | Rhobio | Antimicrobial pseudopeptides |
FR2819514A1 (en) * | 2001-01-12 | 2002-07-19 | Rhobio | ANTIMICROBIAL PSEUDOPEPTIDES |
US7316819B2 (en) | 2001-03-08 | 2008-01-08 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
US8088734B2 (en) | 2003-01-21 | 2012-01-03 | Unigene Laboratories Inc. | Oral delivery of peptides |
US7432045B2 (en) | 2003-12-01 | 2008-10-07 | Wisconsin Alumni Research Foundation | Method of inhibiting influenza infection with antiviral peptides |
US8835377B2 (en) | 2004-06-18 | 2014-09-16 | Ugp Therapeutics, Inc. | Oral delivery of peptide pharmaceutical compositions |
US9504727B2 (en) | 2004-06-18 | 2016-11-29 | Enteris Biopharma, Inc. | Oral delivery of peptide pharmaceutical compositions |
US10377813B2 (en) | 2009-07-14 | 2019-08-13 | Mayo Foundation For Medical Education And Research | Peptide-mediated non-covalent delivery of active agents across the blood-brain barrier |
US20150119340A1 (en) * | 2013-10-29 | 2015-04-30 | Samsung Electronics Co., Ltd. | Fusion peptide and use thereof for cell membrane penetrating |
US10421967B2 (en) | 2014-05-15 | 2019-09-24 | Hoffmann-La Roche Inc. | Oligomers and oligomer conjugates |
US10767181B2 (en) | 2014-05-15 | 2020-09-08 | Hoffmann-La Roche Inc. | Oligomers and oligomer conjugates |
US11591598B2 (en) | 2014-05-15 | 2023-02-28 | Hoffmann-La Roche Inc. | Oligomers and oligomer conjugates |
US10072065B2 (en) | 2015-08-24 | 2018-09-11 | Mayo Foundation For Medical Education And Research | Peptide-mediated delivery of immunoglobulins across the blood-brain barrier |
Also Published As
Publication number | Publication date |
---|---|
AU4281999A (en) | 1999-12-30 |
WO1999064449A3 (en) | 2002-10-24 |
EP1086126A1 (en) | 2001-03-28 |
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