Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-27
2001-10-30
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S078170, C514S002600, C514S054000, C514S183000, C514S307000, C514S553000, C514S578000, C546S085000, C546S150000, C562S101000, C562S104000
Reexamination Certificate
active
06310073
ABSTRACT:
BACKGROUND OF THE INVENTION
Glycosaminoglycans (GAGs) have been shown to be involved with the early steps of the infectious process associated with several pathogens. For example, it is believed that sulfated proteoglycans are used by the infectious agents as anchors or adsorption moieties for invasion of the host cells. Several bacterial and viral infectious agents have been found to use extracellular membrane components, such as GAGs, to access host cells.
Heparan sulfate and/or other sulfated GAGs have been suggested to be involved in the infection process by certain bacteria such as
Streptococcus pyogenes
associated with acute rheumatic fever and poststreptococcal glomerulonephritis,
Chlamydia trachomatis, Staphylococcus aureus
and
Pseudomonas aeruginosa
(cystic fibrosis),
Legionella pneumophila
(Legionnaire's disease), Bordetella pertussis (whooping cough), and Mycoplasma pneumoniae. As one example,
Streptococcus pyogenes
surfaces bind fibronectin, laminin, fibrinogen, nonspecific immunoglobulins A and G, &agr;2-macroglobulin, &bgr;2-microglobulin and albumin. Bacterial components do not bind to epithelial or endothelial cells of the kidney but accumulate on the proteoglycan-rich regions that connect these cells to the underlying connective tissue. Another example,
Chlamydia trachomatis
, is one of the most common sexually transmitted bacterial pathogens in the world. Infection appears to be facilitated by binding of a heparan sulfate-like GAG present on the surface of chlamydia, to a heparan sulfate receptor on the target cell.
Certain types of viri, Herpesviridae, are believed to be associated with HSPG during the infectious process. These viri appear to interact with a cells surface through GAGs found on the proteoglycans of the cell plasma membrane. These GAGs are similar to heparin. Cytomegalovirus (CMV) and Herpes simplex (HSV-1 and HSV-2) are two of the viri which are believed to infect cells via cell surface GAGs.
Although certain agents have been used to suppress infection of hosts by pathogens, there are limitations to their use. For example, the widespread use of antibiotics has increasingly led to the problem of resistant pathogens whose growth can no longer be inhibited by known antibiotics. Thus, the appearance of multi-drug resistant pathogens has prompted a search for new classes of compounds which are structurally and/or functionally different from existing drugs. Drugs having new mechanisms of action could be effective against resistant pathogens, where conventional drugs can no longer be used.
SUMMARY OF THE INVENTION
Methods and compositions which are useful in the treatment of conditions related to glycosaminoglycan (GAG)-associated molecular interactions are presented herein.
In one aspect the invention relates to methods for treating a condition related to a glycosaminoglycan-associated molecular interaction in a subject. The method includes administering to the subject a therapeutically effective amount of a therapeutic compound having the formula:
Q-[-Y
−
X
+
]
n
(I)
wherein Y
−
is an anionic group at physiological pH; Q is a carrier molecule; X
+
is a cationic group; and n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound, or a pharmaceutically acceptable salt or ester thereof, such that the glycosaminoglycan-associated molecular interaction is modulated and the condition is treated. These methods can be used therapeutically to treat a subject, e.g., afflicted with a pathogen, or can be used prophylactically in a subject susceptible to pathogens.
In another embodiment, the therapeutic compound has at least one anionic group covalently attached to a carrier molecule. In another embodiment, the anionic group covalently attached to the carrier molecule is a sulfonate group. Accordingly, the therapeutic compound can have the formula:
Q-[-SO
3
−
X
+
]
n
(II)
wherein Q is a carrier molecule; X
+
is a cationic group; and n is an integer. In another embodiment, the anionic group is a sulfate group. Accordingly, the therapeutic compound can have the formula:
Q-[-OSO
3
−
X
+
]
n
(III)
wherein Q is a carrier molecule; X
+
is a cationic group; and n is an integer. Carrier molecules which can be used include carbohydrates, polymers, peptides, peptide derivatives, aliphatic groups, alicyclic groups, heterocyclic groups, aromatic groups and combinations thereof.
The invention also provides a method for modulating interactions between an infectious agent and a GAG in a subject. The method includes administering to the subject a therapeutically effective amount of a therapeutic compound having the formula:
Q-[-Y
−
X
+
]
n
(I)
wherein Y
−
is an anionic group at physiological pH; Q is a carrier molecule; X
+
is a cationic group; and n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound, or a pharmaceutically acceptable salt or ester thereof.
In another aspect, methods and therapeutic compositions are provided herein for treating a subject afflicted with a disease, e.g., acute rheumatic fever and poststreptococcal glomerulonephritis, caused by infection by bacteria such as
Streptococcus pyogenes, Chlamydia trachomatis, Staphylococcus aureus, Pseudomonas aeruginosa, Legionella pneumophila, Bordetella pertussis
, and
Mycoplasma pneumoniae
, such that the subject afflicted with the disease is treated. The methods include administering to a subject a therapeutically effective amount of a therapeutic compound of formula (I) for treating the infection. The therapeutic compound is not carrageenan, pentosan polysulfate, fucoidan, dextran sulfate, heparin, heparan sulfate or dermatan sulfate.
In yet another aspect, the invention provides methods and therapeutic compositions for treating a subject afflicted with a disease caused by infection of viri via such as Cytomegalovirus (CMV) and Herpes simplex (HSV-1 and HSV-2), such that the subject afflicted with the disease is treated. The methods include administering to a subject a therapeutically effective amount of a therapeutic compound of formula (I) for treating the disease. The therapeutic compound is not a chondroitin sulfate.
In yet a further aspect a packaged pharmaceutical composition for treating a condition related to a glycosaminoglycan-associated molecular interaction or for modulating a GAG-associated molecular interaction, e.g., between a GAG and an infectious agent, is described herein. The packaged composition includes a container holding a therapeutically effective amount of a pharmaceutical composition for treating the condition related to a glycosaminoglycan-associated molecular interaction in a subject. Alternatively, the packaged composition includes a container holding a therapeutically effective amount of a pharmaceutical composition for modulating a GAG-associated molecular interaction. The pharmaceutical composition includes at least one therapeutic compound having the formula:
Q-[-Y
−
X
+
]
n
(I)
wherein Y
−
is an anionic group at physiological pH; Q is a carrier molecule; X
+
is a cationic group; and n is an integer selected such that the biodistribution of the therapeutic compound for an intended target site is not prevented while maintaining activity of the therapeutic compound, or a pharmaceutically acceptable salt or ester thereof. Instructions for using the pharmaceutical composition for treatment of the condition related to a glycosaminoglycan-associated molecular interaction or for modulating the GAG-associated molecular interaction are included in the packaged pharmaceutical composition.
The invention further provides pharmaceutical compositions for treating a condition related to a glycosaminoglycan-associa
Gervais Francine
Green Allan M.
Kisilevsky Robert
Hanley Elizabeth A.
Lahive & Cockfield LLP
Queen's University at Kingston
Russel Jeffrey E.
Triano, III Nicholas P.
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