Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-01-08
2003-03-04
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S015800, C514S016700, C514S021800
Reexamination Certificate
active
06528488
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to methods for treating cystic fibrosis.
Cystic fibrosis is a hereditary disease that affects a number of organs, particularly the lungs and pancreas. The exocrine glands of a cystic fibrosis patient secrete abnormally thick mucous, which blocks the patient's bronchi. As a result, many cystic fibrosis patients have chronic bronchitis; they are also susceptible to pneumonia and other pulmonary infections. In particular, cystic fibrosis patients are susceptible to Pseudomonas infections.
As there is currently no cure for cystic fibrosis, treatments for this disabling disease focus on alleviating the symptoms of the disease. Unfortunately, the infections of many cystic fibrosis patients do not respond to the antibiotics traditionally used to treat pulmonary infections.
SUMMARY OF THE INVENTION
In one aspect, the invention features a method for treating cystic fibrosis in a mammal, such as a human; the method includes administering to the mammal an effective amount of a histatin or a histatin fragment. In preferred methods, the histatin fragment has between 8 and 20 amino acids, inclusive, and more preferably has between 8 and 12 amino acids, inclusive.
For example, the histatin fragment may have the amino acid sequence Ala-Lys-Arg-His-His-Gly-Tyr-Lys-Arg-Lys-Phe-His(SEQ ID NO: 1). Preferably, at least one of the amino acids in this sequence is a D-amino acid. In one preferred method, the fragment has the amino acid sequence D-Ala-D-Lys-D-Arg-D-His-D-His-D-Gly-D-Tyr-D-Lys-D-Arg-D-Lys-D-Phe-D-His.
In another preferred method, the histatin is histatin 5 (SEQ ID NO: 2) (shown in FIG.
2
); preferably, at least one amino acid of the histatin 5 is a D-amino acid. In yet another preferred method, the histatin or histatin fragment has at least one modification selected from the group consisting of an acyl addition at the N-terminus; a carbamyl addition at the N-terminus; and an amide addition at the C-terminus.
In a second aspect, the invention features a method for treating cystic fibrosis in a mammal, such as a human; the method includes administering to the mammal an effective amount of a histatin-related peptide having between 8 and 20 amino acids, inclusive, where the peptide has the amino acid sequence: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23(SEQ ID NO: 3), where R1 is Asp or is absent; R2 is Ser or is absent; R3 is His or is absent; R4 is Ala, His, Leu, or is absent; R5 is Lys, Gln, Arg, Orn, or another basic amino acid; R6 is Arg, Gln, Lys, or another basic amino acid; R7 is His, Phe, Tyr, Leu, or another hydrophobic amino acid; R8 is His, Phe, Tyr, Leu, or another hydrophobic amino acid; R9 is Gly, Lys, Arg, Ser, or a basic amino acid; R10 is Tyr; R11 is Lys, His, Phe, Leu, or another hydrophobic amino acid; R12 is Arg, Gln, Lys, or another basic amino acid; R13 is Lys, Gln, Arg, Orn, another basic amino acid, or is absent; R14 is Phe or is absent; R15 is His, Phe, Tyr, Leu, another hydrophobic amino acid, or is absent; R16 is Glu or is absent; R17 is Lys or is absent; R18 is His or is absent; R19 is His or is absent; R20 is Ser or is absent; R21 is His or is absent; R22 is Arg or is absent; and R23 is Gly or is absent.
In preferred methods, at least one of R7, R8, R11, or R15 is Phe. For example, R7 is Phe; R8 is Phe; R11 is Phe; and/or R 15 is Phe. In one preferred method, all of R7, R8, and R15 are Phe. In other preferred methods, R9 is Lys and/or R11 is His. In other preferred methods, at least one of R7, R8, or R15 is Tyr. Preferably, all of R7, R8, and R15 are Tyr.
In another preferred method, at least one of R5 and R13 is Gln; preferably, both R5 and R15 are Gln. In a different preferred method, at least one of R5 and R13 is Orn; preferably, both R5 and R13 are Orn.
In some preferred methods, all of R1, R2, and R3 are absent. In other preferred methods, both R22 and R23 are absent, all of R20, R21, R22, and R23 are absent, or all of R18, R19, R20, R21, R22, and R23 are absent. Examples of preferred peptides include peptides which have the amino acid sequences: Ala- Lys-Arg-Phe-Phe-Gly-Tyr-Lys-Arg-Lys-Phe-Phe (SEQ ID NO: 4) (P-113-F4.5.12); Ala-Lys-Arg- His-His-Lys-Tyr-Lys-Arg-Lys-Phe-His (SEQ ID NO: 5) (P-113-K6); Ala-Lys-Arg-His-His-Gly- Tyr-His-Arg-Lys-Phe-His (SEQ ID NO: 6) (P-113-H8); Ala-Lys-Arg-His-His-Lys-Tyr-His-Arg- Lys-Phe-His (SEQ ID NO: 7) (P-113-K6H8); Ala-Lys-Arg-Tyr-Tyr-Gly-Tyr-Lys-Arg-Lys-Phe- Tyr-NH
2
(SEQ ID NO: 8) (P-113-Y4.5.12); Ala-Gln-Arg-His-His-Gly-Tyr-Lys-Arg-Gln-Phe-His- NH
2
(SEQ ID NO: 9) (P-113-Q2.10); or Ala- Orn-Arg-Tyr-Tyr-Gly-Tyr-Lys-Arg-Orn-Phe-Tyr-NH
2
(SEQ ID NO: 10) (P-113-K2.10O-H4.5.12Y ).
Preferably, the peptide has at least one modification selected from the group consisting of an acyl addition at the N-terminus; a carbamyl addition at the N-terminus; and an amide addition at the C-terminus.
By “hydrophobic amino acid” is meant an amino acid selected from the group consisting of Ala, Val, Leu, Ile, Phe, Trp, Met, and Thr.
By “basic amino acid” is meant an amino acid selected from the group consisting of Lys, Arg, Orn, Gln, and Asn.
The invention provides effective methods for treating cystic fibrosis. According to the invention, histatins, histatin fragments, and histatin-related peptides can be used to combat Pseudomonas infections and other pulmonary infections in cystic fibrosis patients. Histatin derivatives are effective in treating these infections, even in cases where the infections are resistant to traditional antibiotics.
Other features and advantages of the invention will be apparent from the following description and from the claims.
REFERENCES:
patent: 5631228 (1997-05-01), Oppenheim et al.
patent: 5646119 (1997-07-01), Oppenheim et al.
patent: 5679665 (1997-10-01), Bergamini et al.
patent: 5885965 (1999-03-01), Oppenheim et al.
patent: 5912230 (1999-06-01), Oppenheim et al.
Mendelman et al. Aminoglycoside Penetration, Inactivation, . . . Am. Rev. Respir. Dis. vol. 132, pp. 761-765. 1985.*
Eisenberg et al. A Comparison of Peak Sputum Tobramycin . . . Chest, vol. 111, No. 4, pp. 955-962. Apr. 1997.*
Goldman et al. Human &bgr;-Defensin-1 Is a Salt-Sensitive . . . Cell. vol. 88, pp. 553-560. Feb. 21, 1997.*
Anderson et al., “The In Vitro Antimicrobial Properties of the Polypeptide Compound Polymyxin E1 are Equilvalent to Those of Colistin Sulfate”Pediatric Pulmonolgy Supplement17:423 (1998).
Denton and Wilcox, “Antimicrobial Treatment of Pulmonary Colonization and Infection byPseudomonas Aeruginosain Cystic Fibrosis Patients”Journal of Antimicrobial Chemotherapy40:468-474 (1997).
Hancock, “Peptide Antibiotics”The Lancet349:418/422 (1997).
MacKay et al., “Growth-Inhibitory and Bacterial Effects of Human Parotid Salivary Histidine-Rich Polypeptides onStreptococcus mutans” Infection and Immunity44:695-701 (1984).
Nishikata et al., “Salivary Histatin as an Inhibitor of a Protease Produced by the Oral Bacterium Bacteroides Gingivalis”Biochemical and Biophysical Research Communications174:625-630 (1991).
Oppenheim et al., “Histatins, a Novel Family of Histidine-rich Proteins in Human Parotid Secretion”The Journal of Biological Chemistry263:7472-7476 (1988).
Oppenheim et al., “The Primary Structure and Functional Characterization of the Neutral Histidine-rich Polypeptide from Human Parotid Secretion”The Journal of Biological Chemistry261:1177-1182 (1986).
Pollock et al., “Fungistatic and Fungicidal Activity of Human Parotid Salivary Histidine-Rich Polypeptides andCandida albicans” Infection and Immunity44:702-707 (1984).
Raj et al., “Salivary Histatin 5: Dependence of Sequence, Chain Length, and Helical Conformation for Candidacidal Activity” The Journal of Biological Chemistry 265:3898-3905 (1990).
Santarpia et al., “A Comparison of the Inhibition of Blastospore Viability and Germ-Tube Development in Candida Albicans by Histidine Peptides and Ketoconazole”Archs. Oral Biol.33:567-573 (1988).
Smith and Ramsey, “Aerosol Administration of Antibiotics”Respiration62:19-24 (1995).
Troxler et al., “Structural Relationship Between Hum
Friden Phillip M.
Rothstein David M.
Spacciapoli Peter
Clark & Elbing LLP
Demegen, Inc.
Russel Jeffrey E.
LandOfFree
Method for treating cystic fibrosis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for treating cystic fibrosis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for treating cystic fibrosis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3024515