Self assembling amphiphilic polymers as antiviral agents

{
  "publication_number": "US2010008938A1",
  "country": "US",
  "kind": "A1",
  "title": "Self assembling amphiphilic polymers as antiviral agents",
  "abstract": "There are provided amphiphilic biodegradable copolymers comprising a hydrophilic backbone with pendant aliphatic groups as the hydrophobic component. The polymers form nanoscale molecular aggregates in aqueous environments, which have hydrophobic interiors that are capable of solubilizing insoluble organic compounds and disrupting viral coat proteins. The polymers optionally feature reactive functional groups that provide attachment points for antibodies, ligands, and other targeting moieties which mediate adherence of the aggregate to a viral target.",
  "claims": [
    "1. A method for the treatment or prevention of an infection of an animal by a virus, which comprises administering to said animal a comb polymer consisting essentially of the following structure: comprising a backbone formed of alternating branch-point moieties B and hydrophilic, water-soluble polymer blocks A; and having hydrophobic side chains C and ligands Z attached to the branch-point moieties, wherein: each hydrophobic side chain C is independently selected from the group consisting of C 6 -C 30 linear or branched hydrocarbons optionally substituted with one or more hydrophilic substituents; C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents; and hydrophobic amino acids, peptides and polymers; each ligand Z is independently a ligand having specific binding affinity for the surface of said virus; s is a bond or a spacer moiety; the value of n ranges from 3 to about 100; the average value of p ranges from greater than one to four; and the average value of r ranges from 1 to 8.",
    "2. The method of claim 1, wherein at least one ligand is N-acetyl neuraminic acid or a derivative thereof.",
    "3. The method of claim 2, wherein said ligand is selected from the group consisting of N-acetyl neuraminic acid, neuraminic acid β-methyl glycoside, and 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.",
    "4. The method of claim 1 wherein at least one ligand Z is a peptide, antibody or antibody fragment having specific binding affinity for the surface of said virus.",
    "5. The method of claim 4 wherein said ligand is an Fab or F(ab′) 2 fragment derived from human anti-rabies IgG immune globulin.",
    "6. The method of claim 1, wherein at least one ligand Z is a peptide selected from the group consisting of KDYRGWKHWVYYTC, KDYRGWKOWVYYTC, KGWKHWVYC(NH 2), and KGWKOWVYC(NH 2).",
    "7. The method of any of claims 1 - 6, wherein the water-soluble polymer block A is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), poly(ethyleneimine), poly(vinyl alcohol), poly(vinylpyrrolidone), polysaccharides, and copolymers thereof.",
    "8. The method of claim 7, wherein the polymer block A is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), and copolymers thereof.",
    "9. The method of claim 8, wherein the polymer block A is poly(ethylene glycol).",
    "10. The method of claim 8, wherein the polymer block A has an average length of between 4 and 700 monomer units.",
    "11. The method of claim 1, wherein the polymer has the structure wherein m is 4-700, and Y and Y′ are independently selected from the group consisting of R, OR, COOR, SR, NHR, NRR′, ONHR, NHOR, NRNH 2, NHNHR, NRNHR′, and NHNRR′, wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "12. The method of claim 1, wherein the polymer has the structure wherein m is 4-700, W is O or NH, and Y and Y′ are independently selected from the group consisting of R, COR, COOR, CONHR, CONRR′, CONHOR, CONRNH 2, CONHNHR, CONRNHR′, and CONHNRR′, wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "13. The method of claim 1, wherein the polymer has the structure wherein the moiety D is derived from a diamine having the general structure wherein each X is independently a reactive functional group, p is 0-4, and m is 4-700; and wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "14. The method of claim 1, wherein the polymer has the structure wherein m is 4-700, W is O or NH, and R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "15. The method of claim 1, wherein the polymer has the structure wherein m is 4-700, L is phenylene, C 2 -C 6 alkylene, or benzenedimethylene, W is O or NH, and R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "16. The method of any of claims 1 - 4 wherein the virus is an influenza virus.",
    "17. The method of any of claims 4 - 6 wherein the virus is rabies virus.",
    "18. A peptide selected from the group consisting of KDYRGWKOWVYYTC, KGWKHWVYC(NH 2), and KGWKOWVYC(NH 2).",
    "19. A comb polymer consisting essentially of the following structure: comprising a backbone formed of alternating branch-point moieties B and hydrophilic, water-soluble polymer blocks A; and having hydrophobic side chains C and ligands Z attached to the branch-point moieties, wherein: each hydrophobic side chain C is independently selected from the group consisting of C 6 -C 30 linear or branched hydrocarbons optionally substituted with one or more hydrophilic substituents; C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents; and hydrophobic amino acids, peptides and polymers; each ligand Z is independently a ligand having specific binding affinity for the surface of said virus; s is a bond or a spacer moiety; the value of n ranges from 3 to about 100; the average value of p ranges from greater than one to four; and the average value of r ranges from 1 to 8.",
    "20. The comb polymer of claim 19, wherein at least one ligand is N-acetyl neuraminic acid or a derivative thereof.",
    "21. The comb polymer of claim 20, wherein said ligand is selected from the group consisting of N-acetyl neuraminic acid, neuraminic acid β-methyl glycoside, and 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.",
    "22. The comb polymer of claim 19 wherein at least one ligand Z is a peptide, antibody or antibody fragment having specific binding affinity for the surface of said virus.",
    "23. The comb polymer of claim 22 wherein said ligand is an Fab or F(ab′) 2 fragment derived from human anti-rabies IgG immune globulin.",
    "24. The comb polymer of claim 19, wherein at least one ligand Z is a peptide selected from the group consisting of KDYRGWKHWVYYTC, KDYRGWKOWVYYTC, KGWKHWVYC(NH 2), and KGWKOWVYC(NH 2).",
    "25. The comb polymer of any of claims 19 - 24, wherein the water-soluble polymer block A is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), poly(ethyleneimine), poly(vinyl alcohol), poly(vinylpyrrolidone), polysaccharides, and copolymers thereof.",
    "26. The comb polymer of claim 25, wherein the polymer block A is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), and copolymers thereof.",
    "27. The comb polymer of claim 26, wherein the polymer block A is poly(ethylene glycol).",
    "28. The comb polymer of claim 26, wherein the polymer block A has an average length of between 4 and 700 monomer units.",
    "29. The comb polymer of claim 19, wherein the polymer has the structure wherein m is 4-700, and Y and Y′ are independently selected from the group consisting of R, OR, COOR, SR, NHR, NRR′, ONHR, NHOR, NRNH 2, NHNHR, NRNHR′, and NHNRR′, wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "30. The comb polymer of claim 19, wherein the polymer has the structure wherein m is 4-700, W is O or NH, and Y and Y′ are independently selected from the group consisting of R, COR, COOR, CONHR, CONRR′, CONHOR, CONRNH 2, CONHNHR, CONRNHR′, and CONHNRR′, wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "31. The comb polymer of claim 19, wherein the polymer has the structure wherein the moiety D is derived from a diamine having the general structure wherein each X is independently a reactive functional group, p is 0-4, and m is 4-700; and wherein R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "32. The comb polymer of claim 19 wherein the polymer has the structure wherein m is 4-700, W is O or NH, and R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "33. The comb polymer of claim 19, wherein the polymer has the structure wherein m is 4-700, L is phenylene, C 2 -C 6 alkylene, or benzenedimethylene, W is O or NH, and R and R′ are independently selected from the group consisting of C 6 -C 30 branched or linear hydrocarbons optionally substituted with one or more hydrophilic substituents, C 6 -C 30 cyclic or polycyclic hydrocarbons optionally substituted with one or more hydrophilic substituents, and hydrophobic amino acids, peptides and polymers.",
    "34. The comb polymer of any of claims 19 - 22 wherein the virus is an influenza virus.",
    "35. The comb polymer of any of claims 22 - 24 wherein the virus is rabies virus."
  ],
  "description_excerpt": "The present invention relates to the fields of amphiphilic polymers, and specifically to biocompatible micelle-forming comb-type polymers. The invention also relates to the fields of targeted drug delivery and antiviral agents.\n\nAmphiphilic block copolymers comprising a hydrophobic block and a hydrophilic block have been well studied in recent years, because of their capacity for self-assembly into a variety of nanostructures as the surrounding solvent is varied. See Cameron et al., Can. J. Chem./Rev. Can. Chim. 77:1311-1326 (1999). In aqueous solutions, the hydrophobic compartment of an amphiphilic polymer has a tendency to self-assemble in order to avoid contact with water and to minimize the free interfacial energy of the system. At the same time, the hydrophilic blocks form a hydrated “corona” in the aqueous environment, and so the aggregates maintain a thermodynamically stable structure. The result is a stable, latex-like colloidal suspension of polymer aggregate particles having hydrophobic cores and hydrophilic coronas.\n\nComb-type amphiphilic co-polymers differ from block co-polymers in that the backbone is largely hydrophobic or hydrophilic, with polymer chains of opposite polarity pendant from the backbone rather than incorporated into it. Comb-type copolymers have been prepared with hydrophobic backbones and hydrophilic branches (Mayes et al., U.S. Pat. No. 6,399,700), and also with hydrophilic backbones and hydrophobic branches (Watterson et al., U.S. Pat. No. 6,521,736).",
  "cpc": [
    "A61K 31/795",
    "A61K 47/549",
    "A61K 47/551",
    "A61K 47/64",
    "A61K 47/6841",
    "A61K 47/6907",
    "A61P 31/12",
    "A61P 31/14",
    "A61P 31/16",
    "B82B 3/00",
    "C01G 23/00",
    "C07K 7/08"
  ],
  "ipc": [
    "A61K 38/02",
    "A61K 38/10",
    "A61K 39/395",
    "C08G 63/00"
  ],
  "inventors": [
    "Anil Diwan",
    "Ann Louise Onton",
    "Jayant G. Tatake"
  ],
  "filing_date": "2007-01-22",
  "publication_date": "2010-01-14",
  "priority_date": "2007-01-22",
  "application_number": "US-51841107-A",
  "family_id": "39644738",
  "cited_by_count": 13
}