WO1999036092A2 - Hiv inhibition using ligand for gp60 receptor or albumin receptor on target cells - Google Patents
Hiv inhibition using ligand for gp60 receptor or albumin receptor on target cells Download PDFInfo
- Publication number
- WO1999036092A2 WO1999036092A2 PCT/GB1999/000174 GB9900174W WO9936092A2 WO 1999036092 A2 WO1999036092 A2 WO 1999036092A2 GB 9900174 W GB9900174 W GB 9900174W WO 9936092 A2 WO9936092 A2 WO 9936092A2
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- WIPO (PCT)
- Prior art keywords
- receptor
- albumin
- binding
- hiv
- cells
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- This invention relates to methods and products that may be used to inhibit HIV infection.
- HIV-1 Human immunodeficiency virus type I (HIV-1) entry in target cells is mediated by the viral envelope glycoproteins designated gpl20 and gp41, derived by proteolytic cleavage of the gpl60 precursor.
- gpl20 is the outer surface glycoprotein and contains the site necessary for viral binding to specific target cells.
- gp41 appears to possess one transmembrane domain and is thought to exhibit a multi-role function, being involved in the anchoring of the envelope glycoprotein complex to the viral membrane, the oligomerisation of the envelope glycoprotein and the interaction between viral and cell membranes. Similar processes occurs in other species, with related viruses (e.g. SIV in monkeys) .
- the viral membrane-interaction sequences of gp41 appear to possess a relatively high content of Ala and Gly residues and to be characterised by a short amino-terminal hydrophobic segment which is likely to interact with plasma membranes.
- HSA Human serum albumin
- gp60 or albondin plasma membrane albumin receptor
- transcytosis of a drug such as insulin may be enhanced by formulation with albumin, fragments thereof, gp60 peptide fragments or anti-gp60 antibody.
- This invention is based on the discovery that HIV gp41 interacts with the gp60 receptor.
- Experimental evidence presented below also shows that a receptor for a gp41 fragment exists on the surfaces of T-cells but not on B-cells. Therefore, pharmaceutically-acceptable agents that bind preferentially (which term may also mean mere selectivity, with respect to albumin) to such a receptor, which in use may be any receptor having the binding characteristics of gp60, or another albumin receptor, can be used to inhibit HIV infection.
- Improved selectivity may comprise reduced, substantially zero or zero membrane- binding or lipid-binding. This may exclude charged, e.g. polyanionic, species.
- Fig. 1 shows the interactions of B and T lymphocytes labelled with FPE and albumin.
- Fig. 2 shows the interactions of B and T lymphocytes labelled with FPE, preincubated with albumin and challenged with HIV peptide.
- Figs. 3 and 4 show the interactions of gp60 liposomes labelled with FPE and challenged with HIV peptide and albumin, respectively.
- Fig. 5 shows the binding of HSA and fragments thereof to gp60 liposomes, over a first period of 0.02 sec and a second period of up to 100 sec.
- albumin that has no lipid-binding capacity, e.g. by having its lipid- binding domain (s) deleted or inactivated. This can be done while retaining the function of interaction with the gp60 receptor.
- suitable albumin fragments include those consisting of or including amino-acids 45-65, 45-585, 123-298 or 298-585 of albumin, or a fragment thereof. Certain such fragments may be novel per se, or at least for therapeutic use.
- agents that may be used in the invention are anti-gp60 antibody, gp60 receptor protein, gp41 receptor- binding domain, i.e. gp41 fusion protein without its fusion capability, and fragments thereof that bind to the gp60 receptor. Certain fragments of different parent molecules may show homology. Combinations of any such agents, or combinations of fragments of the same parent molecule, may also be used.
- the invention also envisages the use of materials that have the additional capability of targeting receptor, e.g. CD4, on B/T cells; materials having this function will be well known to those of ordinary skill in the art.
- the gp60 receptor may have two functions, i.e. recognition in addition to transcytosis.
- An agent for use in the present invention may effectively interact with one function, and not necessarily with both.
- the appropriate binding by the active agent of the target receptor may be a function of conformation, or of a structural constraint preventing any change in conformation.
- an active agent may interact with either, or both, of low and high affinity binding sites.
- agents currently preferred for use in the invention are peptides.
- such peptides may comprise at least 4, 5, 6, 8, 10, 15 or 20 amino-acids, or they may be longer, e.g. up to 20, 50 or 100 amino-acids.
- Peptides are generally substantially insoluble. Formulations for administration of such materials are well known, and can be used in this invention.
- the preferred route of administration is by inhalation, e.g. using a metered dose inhaler, buccal, transdermal, etc.
- the amount of the agent to be administered depends on factors routinely considered by those skilled in the art, and can be determined by routine procedures.
- gp60 apparently has a valuable function in transcytosis, it may be desirable to avoid blocking it completely.
- the level of agent that is used in the invention may have to be controlled accordingly.
- the effect of the agent may enhance (by blocking receptors) or be enhanced by the co-administration of a compound that is known to inhibit HIV infection, e.g. an anti-replicase such as AZT.
- AZT anti-replicase
- Membrane systems with well-defined lipid compositions were used in an attempt to characterise the sequence of interactions of the membrane interactions of the viral fusion peptides.
- Synthetic peptides corresponding to the 12 residue N-terminal region of SIV-gp32 (NH 2 -Gly-Val-Phe-Val- Leu-Gly-Phe-Leu-Gly-Phe-Leu-Ala-CONH 2 ; see also SEQ ID NO.l) and the 16 residue sequence corresponding to the N- terminus extremity of gp41 of HIV-1 (NH2-Ala-Val-Gly-Ile- Gly-Ala-Leu-Phe-Leu-Gly-Phe-Leu-Gly-Ala-Ala-Gly-CONH 2 ; see also SEQ ID NO.2) were studied using fluorescence techniques; see Wall et al , Mol.
- Fig. 2 Similar studies performed with the HIV peptides are shown in Fig. 2, and indicate that the relative capacity of each type of lymphocyte for the HIV peptides is similar to that for the albumin molecule. Similarly, a number of cell types such as endothelia, fibroblasts and icroglia that have also been shown to bind albumin have also been studied in an analogous manner and yielded results similar for those of the lymphocytes.
- gp60 was then reconstituted into membranes made up with a well-defined phospholipids mixture (85% PC: 15% PS w/w) followed by labelling with FPE (0.1-0.3M%).
- Gel filtration (Pharmacia- PD10) of the reconstituted vesicles facilitated selection of the reconstituted proteoliposome vesicles on the basis of their diameter (100 nm) .
- ECV304 endothelial cells were grown to confluence in 225 cm 2 flasks then harvested and stored in their culture medium at -18°C. Approx 1 billion cells were collected washed twice with 30ml PBS (lO M sodium and potassium phosphate buffer containing 2.7mM potassium chloride, 137mM sodium chloride, pH 7.4) by precipitation at 4500g for 20 minutes at 4°C. Cells (approx. 4ml) were re-suspended in 6ml PBS containing 1% (v/v) Triton X-100 and then gently stirred on ice for ca. 60 mins. Centrifugation of this mixture at approx.
- PBS lO M sodium and potassium phosphate buffer containing 2.7mM potassium chloride, 137mM sodium chloride, pH 7.4
- the supernatant (10ml) was adjusted to 1% Triton X-100 and 0.2% sodium dodecylsulphate (SDS) . Extraction of the pellet with PBS was repeated and a second aliquot of 10ml of the supernatant adjusted to 1% Triton X- 100 and 0.2% SDS.
- An affinity column was prepared as follows: wheat germ agglutinin from Triticum vulgaris cross-linked to 4% beaded agarose (1ml bed volume) was regenerated by washing with PBS containing 0.5M NaCl, ImM MgCl 2 , ImM MnCl 2 , ImM ZnCl 2 , and ImM CaCl 2 . This solution was removed using 15ml PBS containing 1% Triton X-100 and 0.2% SDS. About 20ml of the cell extract was passed down the WGA-affinity column at a flow rate of approx. 0.2ml. min "1 , then washed with 15ml PBS containing 1% Triton X-100 and 0.2% SDS.
- the GP60 was released from the affinity column by eluting it with PBS buffer containing 1% Triton X-100, 0.2% SDS and 0.5M N- acetylglucosamine. Six 1ml aliquots were collected from the column and the N-acetylglucosamine-containing buffer replaced by PBS buffer containing 0.1% Triton X-100, 0.02% SDS. This was carried out using Centricon-10 ultrafiltration units that were centrifuged at 4500g. Fraction 2 was found to contain significant amounts of gp60 as indicated by ligand blot analysis using I 125 -HSA . Preparation of FPE-labelled GP60 Vesicles and Control Liposomes
- a sample of GP60 which had been stored in liquid nitrogen was thawed and dialysed against approx. 300 volumes of PBS containing 2.0% sodium cholate pH 7.4 overnight.
- a dispersion of PC and PS was prepared by drying a mixture of 17mg PC and 2.8mg PS under argon, washing with 0.5ml ethanol, and then redrying under argon.
- the phospholipid mixture was then dispersed in 1ml PBS containing 2% sodium cholate using a whirlimix (5-10 mins) .
- the sample was subjected to sonication using a microtip probe at power setting 4, 30% duty cycle for 10 mins. This procedure was carried out at 4°C. After sonication the sample was centrifuged at approx. 2000g for 5 mins. Two samples of dispersed phospholipids were prepared in this manner so that one could be used in the preparation of the control liposome sample.
- GP60 vesicles and control liposomes prepared as described above were labelled on their outer leaflet with FPE at a concentration of approx. 0.2% as described by Wall et al , supra .
- the integrity of the membrane vesicles was tested by observing fluorescence changes according to procedures described by Wall et al , supra .
- Rapid kinetic stopped-flow studies were carried out on a SX-17 MV Applied Photophysics spectrofluorimeter apparatus equipped with a 150W xenon arc lamp light source.
- a small aliquot of protein sample was rapidly mixed with an equal volume of gp60 vesicles (or control liposomes) , typically approx. 150 ⁇ l, and the sample illuminated with light of 490nm wavelength. All optical fluorescence emitted by the sample above approx. 512nm was monitored over time. The dead time was estimated to be between 1.2 and 1.5 ms. Consequently, analysis of the time courses was carried out no earlier than 1.8ms after the start of initiating each time course.
- HSA Fragments were carried out in 280mM sucrose, lOmM Tris/HCl pH 7.5 buffer.
- the HSA was obtained from Armour Ltd. and treated to remove any residual bound fatty acids.
- HSA/oleate was prepared by equilibrating a six-fold excess of oleic acid with the HSA sample over approx. 5 hours at room temperature with gentle stirring. Binding of HSA Fragments
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- Proteomics, Peptides & Aminoacids (AREA)
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- Communicable Diseases (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Cell Biology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU21752/99A AU2175299A (en) | 1998-01-19 | 1999-01-19 | Hiv inhibition using ligand for gp60 receptor or albumin receptor on target cells |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9801070.5A GB9801070D0 (en) | 1998-01-19 | 1998-01-19 | HIV inhibition |
GB9801070.5 | 1998-01-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1999036092A2 true WO1999036092A2 (en) | 1999-07-22 |
WO1999036092A3 WO1999036092A3 (en) | 1999-10-28 |
Family
ID=10825503
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/000174 WO1999036092A2 (en) | 1998-01-19 | 1999-01-19 | Hiv inhibition using ligand for gp60 receptor or albumin receptor on target cells |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2175299A (en) |
GB (1) | GB9801070D0 (en) |
WO (1) | WO1999036092A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001046223A1 (en) * | 1999-12-22 | 2001-06-28 | Biovector Solutions Limited | Compounds and use thereof to modify transport across cell membranes |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01217540A (en) * | 1988-02-25 | 1989-08-31 | Toshiba Corp | Document preparing device |
WO1994002505A1 (en) * | 1992-07-20 | 1994-02-03 | Duke University | Compounds which inhibit hiv replication |
WO1997010850A1 (en) * | 1995-09-21 | 1997-03-27 | Andaris Limited | Transcytosis vehicles and enhancers for drug delivery |
-
1998
- 1998-01-19 GB GBGB9801070.5A patent/GB9801070D0/en not_active Ceased
-
1999
- 1999-01-19 WO PCT/GB1999/000174 patent/WO1999036092A2/en active Application Filing
- 1999-01-19 AU AU21752/99A patent/AU2175299A/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01217540A (en) * | 1988-02-25 | 1989-08-31 | Toshiba Corp | Document preparing device |
WO1994002505A1 (en) * | 1992-07-20 | 1994-02-03 | Duke University | Compounds which inhibit hiv replication |
WO1997010850A1 (en) * | 1995-09-21 | 1997-03-27 | Andaris Limited | Transcytosis vehicles and enhancers for drug delivery |
Non-Patent Citations (11)
Title |
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AHMED A E E ET AL: "Purification of a plasma protein that inhibits complement-mediated prevention of immune precipitation." IMMUNOLOGY, (1988) 64 (1), 45-50. , XP002114016 * |
GORDON ET AL.: "The amino-terminal peptide of HIV-1 gp41 interacts with human serum albumin" AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 9, no. 11, November 1993 (1993-11), pages 1145-1156, XP002114010 cited in the application * |
JANSEN R W ET AL: "Potent in vitro anti-human immunodeficiency virus-1 activity of modified human serum albumins." MOLECULAR PHARMACOLOGY, (1991). VOL. 39, NO. 6, PP. 818-23. JOURNAL CODE: NGR. ISSN: 0026-895X., XP002114011 Department of Pharmacology and Therapeutics, Groningen University, The Netherlands. * |
MALIK A B ET AL: "Lectin binding to gp60 decreases specific albumin binding and transport in pulmonary artery endothelial monolayers." 75TH ANNUAL MEETING OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY, ATLANTA, GEORGIA, USA, APRIL 21-25, 1991. FASEB (FE AM SOC EXP BIOL) J. (1991) 5 (4), A754. , XP002114012 * |
NIELSEN H ET AL: "Effect of genetic variation on the fatty acid- binding properties of human serum albumin and proalbumin." BIOCHIMICA ET BIOPHYSICA ACTA, (1997 OCT 17) 1342 (2) 191-204. , XP002114009 * |
PATENT ABSTRACTS OF JAPAN vol. 14, no. 539 (C-0782), 28 November 1990 (1990-11-28) & JP 01 217540 A (TONEN CORP), 10 September 1990 (1990-09-10) & DATABASE WPI Week 9042 Derwent Publications Ltd., London, GB; AN 90-317325 "New human serum albumin fragments-used to bond to medicines and for stable folding of protein(s)" * |
PEREIRA F B ET AL: "Membrane fusion induced by the HIV type 1 fusion peptide: modulation by factors affecting glycoprotein 41 activity and potential anti- HIV compounds." AIDS RESEARCH AND HUMAN RETROVIRUSES, (1997). VOL. 13, NO. 14, PP. 1203-11. JOURNAL CODE: ART. ISSN: 0889-2229., XP002114018 Department of Biochemistry and Molecular Biology (Biomembrane Laboratory-CSIC), University of the Basque Country, Bilbao, Spain. * |
SCHNITZER, JAN E. (1) ET AL: "Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium." AMERICAN JOURNAL OF PHYSIOLOGY, (1992) VOL. 263, NO. 6 PART 2, PP. H1872-H1879. , XP002114017 * |
SCHNITZER, JAN E. (1) ET AL: "Antibodies to the albumin binding protein, albondin, inhibit transvascular transport of albumin in the rat lung." FASEB JOURNAL, (1993) VOL. 7, NO. 3-4, PP. A902. MEETING INFO.: MEETING OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY ON EXPERIMENTAL BIOLOGY '93 NEW ORLEANS, LOUISIANA, USA MARCH 28-APRIL 1, 1993 , XP002114013 * |
SLEPUSHKIN V A ET AL: "Inhibition of human immunodeficiency virus type 1 ( HIV -1) penetration into target cells by synthetic peptides mimicking the N-terminus of the HIV -1 transmembrane glycoprotein." VIROLOGY, (1993). VOL. 194, NO. 1, PP. 294-301. JOURNAL CODE: XEA. ISSN: 0042-6822., XP002114015 D. I. Ivanovsky Institute of Virology, Russian Academy of Medical Sciences, Moscow. * |
TIRUPPATHI, CHINNASWAMY (1) ET AL: "Isolation and characterization of a cell surface albumin -bindin protein from vascular endothelial cells." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, (1996) VOL. 93, NO. 1, PP. 250-254. , XP002114014 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001046223A1 (en) * | 1999-12-22 | 2001-06-28 | Biovector Solutions Limited | Compounds and use thereof to modify transport across cell membranes |
AU782280B2 (en) * | 1999-12-22 | 2005-07-14 | Advanced Protein Systems Limited | Compounds and use thereof to modify transport across cell membranes |
US7049295B2 (en) | 1999-12-22 | 2006-05-23 | Biotransys Limited | Compounds and use thereof to modify transport across cell membranes |
CN100360553C (en) * | 1999-12-22 | 2008-01-09 | 生物转换系统有限公司 | Compounds and use thereof to modify transport across cell membranes |
Also Published As
Publication number | Publication date |
---|---|
WO1999036092A3 (en) | 1999-10-28 |
GB9801070D0 (en) | 1998-03-18 |
AU2175299A (en) | 1999-08-02 |
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