Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-03-06
2002-10-08
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S002600, C514S012200, C514S014800
Reexamination Certificate
active
06462070
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a conjugate which includes a photosensitizer and a targeting moiety, and methods of using the conjugate.
BACKGROUND OF THE INVENTION
Infectious diseases remain an unsolved problem, due largely to emergence of multiply-antibiotic resistant strains of bacteria, newly discovered viral diseases, and the spread of fungal and protozoan diseases.
Advanced periodontal disease is one of a large number of oral infectious diseases, and is the principal cause of tooth loss in those over 30 years old. Periodontal diseases arise from the interaction between bacterial cells and their products in dental plaque, and the host defense mechanisms (Antczak-Bouckoms, A., (1994),
J. Dent. Educ.
58:625-640). Current treatments often rely on mechanical removal of the plaque and bacteria, which can be inefficient (Unsal E. et al., (1995),
J. Periodontol.
66:47-51), or antibiotic therapy, which can lead to bacterial resistance (Olsvik, B. et al., (1995),
J. Clin. Periodontol.
22:391-396).
Photodynamic therapy (PDT) has been proposed as an attractive method of eliminating oral bacteria and bacteria in topical and gastrointestinal infections because these sites are relatively accessible to illumination. For example, fiber optics can be used to deliver light into the dental pocket (Wilson, M., (1993),
J. Appl. Bacteriol.
75:299-306).
SUMMARY OF THE INVENTION
The inventor has discovered that classes of molecules not hither to used as targeting moieties for photosensitizers, can be used to target photosensitizers.
Accordingly, the invention features, a conjugate molecule which includes a photosensitizer coupled to a non-pair member (NPM) moiety, e.g., an NPM-polypeptide.
In embodiments in which the targeting moiety includes a polypeptide, the targeting moiety can be a linear, branched, or cyclic polypeptide.
In preferred embodiments, the targeting moiety includes a small anti-microbial peptide (SAMP). Histatins, defensins, cecropins, magainins, Gram positive bacteriocins, and peptide antibiotics can be SAMP's. In preferred embodiments, the targeting moiety includes a bacterial, fungal, animal, e.g., mammalian, e.g., human, SAMP, or an active fragment or analog thereof.
In preferred embodiments the targeting moiety includes a defensin, or an active fragment or analog thereof. By way of example the defensin can be: a human defensin, e.g., HNP-1, -2, -3, or -4; a guinea pig defensin, e.g., GPNP; a rabbit defensin, e.g., rabbit NP-1, -2, -3A, -3B, or 5; a rat defensin, e.g., rat NP-1, -2, -3, or -4; murine cryptin; bovine granulocyte bactenecin or indolicidin; or bovine seminal plasmin.
In preferred embodiments, the targeting moiety includes a SAMP of insect origin, or an active fragment or analog thereof, e.g., a cecropin from Cecropia moths, bumble bees, fruit flies, or other insects, an apidaecin from honeybees, or an adropin from fruit flies.
In preferred embodiments, the targeting moiety includes a SAMP of amphibial origin, or an active fragment or analog thereof, e.g., a magainin, a PGLA, a XPF, a LPF, a CPG, a PGQ, a bombinin, a bombinin-like peptide BLP-1, -2, -3, or -4, or a brevinin.
In preferred embodiments the targeting moiety includes a SAMP from an invertebrate, or an active fragment, or analog thereof, e.g., tachyplesin I, II, or III, or polyphemusin I or II, from horseshoe crab. In preferred embodiments, the targeting moiety is from a fish, e.g., pardaxin.
In preferred embodiments, the targeting moiety includes a bacteriocin, more preferably a Gram positive bacteriocin, or an active fragment, or analog thereof, e.g., a nisin, a subtilin, epidermin, gallidermin, salivarin, or a lacticin.
In preferred embodiments, the targeting moiety includes a peptide antibiotic, or an active fragment or analog thereof, e.g., a tyrocidin, or a bacitracin.
In preferred embodiments the targeting moiety includes a histatin, or an active fragment or analog thereof, e.g., histatin-1 through -8, preferably histatin-1, -3, or -5. In preferred embodiments the targeting moiety includes histatin-5 residues 13-24, or corresponding residues from other histatins. In preferred embodiments the targeting moiety includes a histatin molecule which has been engineered to include an internal duplication.
In preferred embodiments, the targeting moiety includes a polypeptide having an affinity for a polysaccharide target, e.g., a lectin. By way of example the lectin can be a seed, bean, root, bark, seaweed, fungal, bacteria, or invertebrate lectin. In preferred embodiments, the targeting moiety includes a plant polypeptide, e.g., a lectin from jack bean, e.g., concanavalin A, or a lectin from a lentil,
Lens culinaris.
In preferred embodiments, the targeting moiety includes a salivary polypeptide, or an active fragment or analog thereof. Examples of salivary polypeptides are the histatins, e.g., histatin-1 through -8, or more preferably, histatin-1, -3, or -5. In preferred embodiments the targeting moiety includes histatin-5 residues 13-24, or corresponding residues from other histatins. In preferred embodiments the targeting moiety includes a histatin molecule which has been engineered to include an internal duplication.
In preferred embodiments, the targeting moiety includes a Gram negative bacteriocin, e.g., colicin B, colicin E1, or colicin Ia.
In preferred embodiments the targeting moiety includes bacterially elaborated polypeptide, e.g., nisin, subtilin, epidermin, gallidermin, salivarin, or lacticin.
In preferred embodiments the targeting moiety includes a molecule, e.g., a peptide, other than an antibody or either member of a receptor-ligand pair.
In preferred embodiments, the conjugate does not include, e.g., it is not coupled, e.g., covalently or non-covalently coupled to: a PM; an antibody; an enzyme; a hormone; a receptor on a cell surface; or the ligand for a receptor on a cell surface.
In preferred embodiments the targeting moiety includes a peptide in which at least 10, 20, 30, 40, 50, 60, 70, 80, 90% of the amino acid residues are of one amino acid residue, e.g., a positively charged amino acid residue, e.g., a lysine reside, an arginine residue, or an ornithine residue. Particularly preferred targeting moieties are polyamino acids, e.g., polylysine, polyarginine, or polyornithine.
In preferred embodiments the targeting moiety: is cationic; has a net positive charge of +1, +2 or +3 per molecule; has a net positive charge equal to or greater than +4; includes a positively charged amino acid residue, e.g, lysine; includes at least 2, 3, 4, or more positively charged amino acid residues, e.g, a lysine, arginine, or ornithine residue.
In other embodiments the targeting moiety: is anionic; has a net negative charge of -1, -2 or -3 per molecule; has a net negative charge equal to or greater than -4; includes a negatively charged amino acid residue, e.g, aspartic acid or glutamic acid; includes at least 2, 3, 4, or more negatively charged amino acid residues, e.g, glutamic; includes at least 10, 20, 30, 40, or 50% or more negatively charged amino acid residues, e.g. aspartic acid, or glutamic acid.
In preferred embodiments the targeting moiety: is approximately neutral in charge; includes at least 50, 60, 70, 80, or 90% amino acid residues which are neutral amino acid residues, such as serine, threonine, alanine, methionine, cysteine, or valine.
In preferred embodiments the targeting moiety has a molecular weight of more than 1200, 1800, 2400, 3000, 6000, 10,000, 25,000, 50,000, 100,000, or 200,000 daltons. In preferred embodiments the targeting moiety has a molecular weight of less than 250,000, 150,000, 60,000, 25,000, 10,000, 8,000, or 6,000 daltons. In particularly preferred embodiments the molecular weight of the targeting moiety is between 300 and 1800, 600 and 2400, 1200 and 6,000, 5,000 and 8,000, 8,000 and 15,000, 15,000 and 30,000, 35,000 and 70,000, 70,000 and 150,000, or 150,000 and 300,000 daltons.
In preferred embodiments the targeting moiety includes a peptide at least 3, 6, 12, 18, 24, 30, 60, 100, 250, 500, 1,000, or 2,500 resi
Hamblin Michael R.
Hasan Tayyaba
Soukos Nikos
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Leahy Amy
The General Hospital Corporation
Travers Russell
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