US2016361423A1PendingUtilityA1
Carbohydrate-lipid constructs and their use in preventing or treating viral infection
Est. expiryApr 27, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Henry
A61K 31/7028A61K 35/18A61K 31/70A61P 31/12A61K 31/702A61K 31/685A61P 31/18A61K 47/481
61
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Claims
Abstract
The invention relates to selected carbohydrate-lipid constructs and their use as mimics of ligands for receptors expressed by a virus. In particular, the invention relates to the use of selected carbohydrate-lipid constructs in methods of inhibiting virus infection and/or promoting clearance of virus from infected subjects. Carbohydrate-lipid constructs selected for use in these methods where the virus is Human Immunodeficiency Virus (HIV) are provided.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting infection of the cells of a subject by a virus by administering to the subject an amount of carbohydrate-lipid construct of the formula F-S 1 -S 2 -L where:
F is selected from the group consisting of glycotopes of ligands for one or more receptors expressed by the virus; S 1 -S 2 is a spacer linking F to L; and L is a lipid selected from the group consisting of diacyl- and dialkyl-glycerolipids, including glycerophospholipids.
2 . The method of claim 1 where the amount is effective to inhibit binding of the receptor expressed by the virus to the cell surface expressed ligand.
3 . The method of claim 1 where the receptor is expressed by the human immunodeficiency virus (HIV).
4 . The method of claim 1 where S 1 is a C 2-5 -aminoalkyl selected from the group consisting of: 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl.
5 . The method of claim 1 where S 2 is selected from the group consisting of: —CO(CH 2 ) 3 CO—, —CO(CH 2 ) 4 CO-(adipate), and —CO(CH 2 ) 5 CO—.
6 . The method of claim 1 where L is selected from the group consisting of: diacylglycerolipids, phosphatidate, phosphatidyl choline, phosphatidyl, ethanolamine, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol; and diphosphatidyl glycerol derived from one or more of trans-3-hexadecenoic acid, cis-5-hexadecenoic acid, cis-7-hexadecenoic acid, cis-9-hexadecenoic acid, cis-6-octadecenoic acid, cis-9-octadecenoic acid, trans-9-octadecenoic acid, trans-11-octadecenoic acid, cis-11-octadecenoic acid, cis-11-eicosenioic acid or cis-13-docsenoic acid.
7 . The method of claim 6 where the lipid is derived from one or more cis-destaurated fatty acids.
8 . The method of claim 1 where L is selected from the group consisting of: 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) and 1,2-O-distearyl-sn-glycero-3-phosphatidylethanolamine (DSPE); and rac-1,2-dioleoylglycerol (DOG).
9 . The method of claim 1 where L is a glycerophospholipid and the construct includes the substructure:
where X is H or C, * is other than H and n is an integer 2 to 5.
10 . The method of claim 1 where L is a glycerophospholipid and the construct includes the substructure:
where:
X is H;
R 1 is a C p -alkyl glycoside;
R 2 and R 3 are independently selected from the group consisting of: trans-3-hexadecenal, cis-5-hexadecenal, cis-7-hexadecenal, cis-9-hexadecenal, cis-6-octadecenal, cis-9-octadecenal, trans-9-octadecenal, trans-11-octadecenal, cis-11-octadecenal, cis-11-eicosenal or cis-13-docsenal;
n is 2 to 5; and
p is 2 or 3.
11 . The method of claim 10 where the glycoside is 1-O—(O-α-D-galactopyranosyl-(I→4)-O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosyl (Gb 3 ), n is 4 and p is 3.
12 . The method of claim 1 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DOPE (I) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
13 . The method of claim 1 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DSPE (II) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
14 . The method of claim 1 where the carbohydrate-lipid construct has the structure:
designated Gb3-sp2-Ad-DOPE (III) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
15 . The method of claim 1 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp2-Ad-DSPE (IV) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
16 . The method of claim 1 where the administering to the subject is by intravascular injection.
17 . The method of claim 1 where the administering is by intravenous injection.
18 . The method of claim 1 where the administering to the subject is to provide a concentration in the plasma of the subject of greater than 400 μM.
19 . The method of claim 1 where the administering to the subject is by topical application.
20 . The method of claim 1 where the administering to the subject is by topical application as a cream or suppository.
21 . A method of promoting clearance of a virus from an infected subject by administering to the subject an amount of carbohydrate-lipid construct of the formula F-S 1 -S 2 -L where:
F is selected from the group consisting of glycotopes of ligands for one or more receptors expressed by the virus; S 1 -S 2 is a spacer linking F to L; and L is a lipid selected from the group consisting of diacyl- and dialkyl-glycerolipids, including glycerophospholipids.
22 . The method of claim 21 where the administering to the subject is by intravascular injection.
23 . The method of claim 21 where the administering is by intravenous injection.
24 . The method of claim 21 where the amount is sufficient to promote partitioning of the carbohydrate-lipid construct into the membranes of cells of the vascular system.
25 . The method of claim 21 where the administering to the subject is to provide an initial concentration in the plasma of the subject of greater than 400 μM.
26 . The method of claim 21 where the virus is human immunodeficiency virus (HIV).
27 . The method of claim 21 where S 1 -S 2 is selected to provide a carbohydrate-lipid construct that partitions into a lipid bi-layer when a solution of the construct is contacted with the lipid bi-layer.
28 . The method of claim 21 where S 1 is a C 2-5 -aminoalkyl selected from, the group consisting of: 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl.
29 . The method of claim 21 where S 2 is selected from the group consisting of: —CO(CH 2 ) 3 CO—, —CO(CH 2 ) 4 CO-(adipate), —CO(CH 2 ) 5 CO— and —CO(CH 2 ) 5 NHCO(CH 2 ) 5 CO—.
30 . The method of claim 21 where L is selected from the group consisting of: diacylglycerolipids, phosphatidate, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, and diphosphatidyl glycerol derived from one or more of trans-3-hexadecenoic acid, cis-5-hexadecenoic acid, cis-7-hexadecenoic acid, cis-9-hexadecenoic acid, cis-6-octadecenoic acid, cis-9-octadecenoic acid, trans-9-octadecenoic acid, trans-11-octadecenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid or cis-13-docsenoic acid.
31 . The method of claim 30 where the lipid is derived from one or more cis-destaurated fatty acids.
32 . The method of claim 21 where L is selected from the group consisting of: 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) and 1,2-O-distearyl-sn-glycero-3-phosphatidylethanolamine (DSPE); and rac-1,2-dioleoylglycerol (DOG).
33 . The method of claim 21 where L is a glycerophospholipid and the construct includes the substructure:
where X is H or C, * is other than H and n is an integer 2 to 5.
34 . The method of claim 21 where L is a glycerophospholipid and the construct includes the substructure:
where:
X is H;
R 1 is a C p -alkyl glycoside;
R 2 and R 3 are independently selected from the group consisting of: trans-3-hexadecenal, cis-5-hexadecenal, cis-7-hexadecenal, cis-9-hexadecenal, cis-6-octadecenal, cis-9-octadecenal, trans-9-octadecenal, trans-11-octadecenal, cis-11-octadecenal, cis-11-eicosenal or cis-13-docsenal;
n is 2 to 5; and
p is 2 or 3.
35 . The method of claim 34 where the glycoside is 1-O—(O-α-D-galactopyranosyl-(1→4)-O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosyl (Gb 3 ), n is 4 and p is 3.
36 . The method of claim 22 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DOPE (I) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
37 . The method of claim 22 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DSPE (II) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
38 . The method of claim 22 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp2-Ad-DOPE (III) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
39 . The method of claim 22 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp2-Ad-DSPE (IV) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
40 . A pharmaceutical preparation for administration to a subject comprising a receptor binding carbohydrate-lipid construct of the formula F-S 1 -S 2 -L where:
F is selected from the group consisting of glycotopes of ligands for one or more receptors; Si-S 2 is a spacer linking F to L; and L is a lipid selected from the group consisting of diacyl- and dialkyl-glycerolipids, including glycerophospholipids; and pharmaceutically acceptable formulants.
41 . The pharmaceutical preparation of claim 40 where the one or more receptors are expressed by a virus.
42 . The pharmaceutical preparation of claim 40 where the one or more receptors are expressed by the human immunodeficiency virus (HIV).
43 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is in the form of a cream or suppository.
44 . The pharmaceutical preparation of claim 40 where Si-S 2 is selected to provide a carbohydrate-lipid construct that partitions into a lipid bi-layer when a solution of the construct is contacted with the lipid bi-layer.
45 . The pharmaceutical preparation of claim 40 where Si is a C 2-5 -aminoalkyl selected from the group consisting of: 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl.
46 . The pharmaceutical preparation of claim 40 where S 2 is selected from the group consisting of: —CO(CH 2 ) 3 CO—, —CO(CH 2 ) 4 CO— (adipate), and —CO(CH 2 ) 5 CO—.
47 . The pharmaceutical preparation of claim 40 where L is selected from the group consisting of:
diacylglycerolipids, phosphatidate, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, and diphosphatidyl glycerol derived from one or more of trans-3-hexadecenoic acid, cis-5-hexadecenoic acid, cis-7-hexadecenoic acid, cis-9-hexadecenoic acid, cis-6-octadecenoic acid, cis-9-octadecenoic acid, trans-9-octadecenoic acid, trans-11-octadecenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid or cis-13-docsenoic acid.
48 . The pharmaceutical preparation of claim 47 where the lipid is derived from one or more cis-destaurated fatty acids.
49 . The pharmaceutical preparation of claim 40 where L is selected from the group consisting of: 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) and 1,2-O-distearyl-sn-glycero-3-phosphatidylethanolamine (DSPE); and rac-1,2-dioleoylglycerol (DOG).
50 . The pharmaceutical preparation of claim 40 where L is a glycerophospholipid and the construct includes the substructure:
where X is H or C, * is other than H and n is an integer 2 to 5.
51 . The pharmaceutical preparation of claim 40 where L is a glycerophospholipid and the construct includes the substructure:
where:
X is H;
R 1 is a C p -alkyl glycoside;
R 2 and R 3 are independently selected from the group consisting of: trans-3-hexadecenal, cis-5-hexadecenal, cis-7-hexadecenal, cis-9-hexadecenal, cis-6-octadecenal, cis-9-octadecenal, trans-9-octadecenal, trans-11-octadecenal, cis-11-octadecenal, cis-11-eicosenal or cis-13-docsenal;
n is 2 to 5; and
p is 2 or 3.
52 . The pharmaceutical preparation of claim 51 where the glycoside is 1-O—(O-α-D-galactopyranosyl-(1→4)-O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosyl (Gb 3 ), n is 4 and p is 3.
53 . The pharmaceutical preparation of claim 40 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DOPE (I) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
54 . The pharmaceutical preparation of claim 40 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp3-Ad-DSPE (II) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
55 . The pharmaceutical preparation of claim 40 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp2-Ad-DOPE (III) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
56 . The pharmaceutical preparation of claim 40 where the carbohydrate-lipid construct has the structure:
designated Gb 3 -sp2-Ad-DSPE (IV) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
57 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated for administration by intravascular injection.
58 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated for administration by intravenous injection.
59 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated as an aqueous formulation.
60 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation comprises a suspension of red blood cells of the subject modified to incorporate the receptor binding carbohydrate-lipid construct.
61 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated as an aqueous formulation for administration by intravenous injection and identified for use in inhibiting HIV infection and/or promoting clearance of HIV from infected subjects.
62 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated for administration as a cream or suppository.
63 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated for administration as a cream.
64 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated as an aqueous formulation.
65 . The pharmaceutical preparation of claim 40 where the pharmaceutical preparation is formulated as an aqueous formulation for administration as a cream and identified for use in inhibiting or preventing HIV infection.
66 . The carbohydrate-lipid construct of the structure:
designated Gb 3 -sp3-Ad-DOPE (I) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
67 . The carbohydrate-lipid construct of the structure:
designated Gb 3 -sp3-Ad-DSPE (II) and where M is typically U, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
68 . The carbohydrate-lipid construct of the structure:
designated Gb 3 -sp2-Ad-DOPE (III) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
69 . The carbohydrate-lipid construct of the structure:
designated Gb 3 -sp2-Ad-DSPE (IV) and where M is typically H, but may be replaced by another monovalent cation such as Na + , K + , NH 4 + or triethylamine ([NH(CH 2 CH 3 ) 3 ] + ).
70 . The use of at least one of the carbohydrate-lipid constructs of claim 66 in the manufacture of a pharmaceutical preparation for the inhibition of HIV infection of the cells of a subject.
71 . The use of at least one of the carbohydrate-lipid constructs of claim 66 in the manufacture of a pharmaceutical preparation for promoting clearance of HIV from an infected subject.
72 . A pharmaceutical preparation for use in the prevention of HIV infection by topical application comprising a carbohydrate-lipid construct selected from the group consisting of: Gb 3 -sp3-Ad-DOPE (I); Gb 3 -sp3-Ad-DSPE (II); Gb 3 -sp2-Ad-DOPE (III); and Gb 3 -sp2-Ad-DSPE (IV).Cited by (0)
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