Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-06-22
2003-04-22
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S015800, C514S016700, C514S018700, C530S323000, C530S327000, C530S328000, C530S329000, C530S330000, C530S331000
Reexamination Certificate
active
06551998
ABSTRACT:
BACKGROUND OF THE INVENTION
The worldwide use of antibiotics to treat infectious diseases in humans and animals has grown dramatically over the last forty years. In 1954, two million pounds of antibiotics were produced in the United States. Today, the figure exceeds 50 million pounds. According to the Centers Disease Control (CDC), humans consume 235 million doses of antibiotics annually. Widespread misuse or overuse of antibiotics has fostered the spread of antibiotic resistance and has contributed to the development of a serious public health problem. Antibiotic resistance occurs when bacteria that cause infection are not killed by the antibiotics taken to stop the infection. The bacteria survive and continue to multiply, causing more harm. For example, the bacterium
Staphylococcus aureus
is a major cause of hospital acquired infections that, historically, responded satisfactorily to the antibiotic vancomycin. Recently, however, many strains of
S. aureus
have been found to be resistant to vancomycin. Moreover, the death rate for some communicable diseases such as tuberculosis have started to rise again, in part because of increases in bacterial resistance to antibiotics.
The occurrence of antibiotic resistance in bacteria has spurred the search for new antibacterial compounds. In large part, this search for new drugs has focused on identifying the defense molecules that plants and animals themselves produce to fight infections. One group of compounds that has gained researchers' attention are the peptide antibiotics.
Both plants and animals fight infection by producing peptides that have antimicrobial and antiviral activity. They are typically characterized by their small size (less than 35 amino acid residues) and positive charge. It is hypothesized that these molecules disrupt cellular membranes of the bacteria. To that end, various classes of these antimicrobial/antiviral peptides have been isolated from tissues of plants bacteria, fungi, and animals. See A. J Deluca et. al. Antimicrob. Agents & Chemother., 43, 1-11 (review). Plant-derived antimicrobial peptides include the plant defensins. Bacterial and fungal-derived antimicrobial peptides include, among others, the iturins, syringomicins, nikkomicins, polyoxins.
Mammalian-derived antimicrobial peptides include the defensins, protegrins, and gallinacins. Defensins are small cationic proteins that are isolated from various organisms. They electrostatically bond to membranes, causing the formation of multimeric pores and the leakage of essential minerals and metabolites. Related to the defensins are the protegrins and gallinacins. Protegrins are cationic, cysteine-rich molecules that are isolated from porcine leucocytes. They form weakly selective ionic channels that allow membrane permeation of anions and small cations. Gallinacins are cationic, arginine and lysine-rich molecules that are isolated from chicken leucocytes. At least several patents have issued on the defensins, including U.S. Pat. Nos. 4,705,777; 4,659,692; and 4,543,252; EP 193351; EP 185250; EP 162161; and WO 8911291.
Insect-derived antimicrobial peptides include the cecropins. Cecropins are cationic linear peptides that are isolated from the hemolymph of the giant silk moth,
Hyalopora ceropia
. They have been observed to form time-variant voltage dependant ion channels in planar lipid membranes. Cecropins are not lethal to mammals and have been administered safely to animals. Cecropins are active fungicides against pathogenic Aspergillus species at between 25-100 &mgr;g/mL. Cecropin A exhibited total killing of
Fusarium moniliforme
and
Fusarium oxysporum
at 12.4 &mgr;g/mL. Several of the cecropins have been isolated and described in the patent literature. See, e.g., WO 8900199; WO 8805826; WO 8604356; and WO 8805826.
Amphibian-derived antimicrobial peptides include dermaseptin and the magainins. Dermaseptins are linear, cationic, lysine-rich peptides that are isolated from the South American arboreal frog,
Phyllomedusa sauvagii
. They are believed to lyse micro-organisms by interacting with lipid bilayers, leading to alterations in membrane function responsible for osmotic balance. Isolated from the African clawed frog
Xenopus laevis
, the magainins are helical ionophores that dissipate in cell membranes, causing lysis.
Although many of the antimicrobial peptides and peptide classes discussed in the previous paragraphs exhibit promising biological activity, their widespread adoption for use as pharmacological agents to fight infections in mammals has been somewhat slow. This is due in part to peptides possessing amide bonds that are hydrolyzable in the gut. In short, natural and synthetic peptides are not transported across the intestinal barrier.
As a result, there remains a need for peptide antibiotic derivatives that are less-hydrolyzable or non-hydrolyzable in the gut and that can be transported across the intestinal barrier. There is an additional need to identify compounds that possess the biological activity of antimicrobial peptides. There is also a need for pharmacological tools for the further study of the physiological processes associated with peptide-mediated disruption of cell membrane function and the use of antimicrobial peptides to fight infections in mammals.
SUMMARY OF THE INVENTION
This and other needs are met by the present invention. The present invention is directed to compounds that exhibit reduced levels of hydrolysis in the gut but that exhibit the biological activity of peptide antibiotics, particularly the antimicrobial peptides.
Accordingly there is provided a compound of the invention which is a compound of formula (I):
R
1
—X—R
2
(I)
wherein
X is a peptide comprising of from about 4 to about 10 amino acids, wherein at least one of the amide (—CONH—) linkages is replaced by —CR
a
C
b
NR
c
—;
R
a
, R
b
, and R
c
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
6
)alkoxycarbonyl, aryl, heterocycle; and
R
1
and R
2
are each independently hydrogen, a saccharide, a lipid, a solubilizing agent, or a protecting group;
or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
Additionally, the invention provides a therapeutic method for preventing or treating antimicrobial infections in a mammal (e.g., a human) in need of such treatment comprising administering to the mammal an effective amount of a compound of the invention.
The invention also provides a compound of formula (I) for use in medical therapy (preferably for use in treating and/or preventing antimicrobial infections in a mammal), as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with an antimicrobial infection.
REFERENCES:
patent: 4543252 (1985-09-01), Lehrer et al.
patent: 4559157 (1985-12-01), Smith et al.
patent: 4608392 (1986-08-01), Jacquet et al.
patent: 4659692 (1987-04-01), Lehrer et al.
patent: 4705777 (1987-11-01), Lehrer et al.
patent: 4820508 (1989-04-01), Wortzman
patent: 4938949 (1990-07-01), Borch et al.
patent: 4992478 (1991-02-01), Geria
patent: 5854211 (1998-12-01), Johansen et al.
patent: 0162161 (1985-11-01), None
patent: 0193351 (1986-09-01), None
patent: 443559 (1991-08-01), None
patent: 89/11291 (1989-11-01), None
patent: 96/34005 (1996-10-01), None
patent: 97/03995 (1997-02-01), None
De Lucca, A.J., et al., “Antifungal Peptides: Novel Therapeutic Compounds against Emerging Pathogens”,Antimicrobial Agents and Chemotherapy, 43(1), pp. 1-11, (Jan. 1999).
Oh, J.E., et al., “Design, systhesis and characterization of antimicrobial pseudopeptides corresponding to membrane-active peptide”,Journal of Peptide Research, 54(2), pp. 129-36, (Aug. 1999).
Spatola, A.F., “Peptide backbone modifications: a structure-activit
Spatola Arno F.
Vogel David M.
Wen James Jun
Russel Jeffrey E.
Schwegman Lundberg Woessner & Kluth P.A.
University of Louisville Research Foundation Inc.
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