Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Peptides with at least one nonpeptide bond other than a...
Reexamination Certificate
2000-02-11
2004-01-27
Baker, Maurie Garcia (Department: 1639)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Peptides with at least one nonpeptide bond other than a...
C514S017400, C514S018700, C514S019300, C514S020800, C530S324000, C530S329000, C530S330000, C530S331000, C530S332000, C530S333000, C530S350000
Reexamination Certificate
active
06683154
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to antimicrobial compositions containing active ingredients which are oligomers and/or polymers of &bgr;-amino acids.
DESCRIPTION OF THE PRIOR ART
Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low molecular weight catalysts and receptors. Most biological systems, however, rely almost exclusively on large polymers such as proteins and RNA to perform complex chemical functions.
Proteins and RNA are unique in their ability to adopt compact, well-ordered conformations. These two biopolymers are unique also because they can perform complex chemical operations (e.g., catalysis, highly selective recognition, etc.). Folding is linked to function in both proteins and RNA because the creation of an “active site” requires proper positioning of reactive groups. Consequently, there has been a long-felt need to identify synthetic polymer backbones which display discrete and predictable folding propensities (hereinafter referred to as “foldamers”) to mimic natural biological systems. Such backbones will provide molecular “tools” to probe the functionality of large-molecule interactions (e.g. protein-protein and protein-RNA interactions).
Much work on &bgr;-amino acids and peptides synthesized therefrom has been performed by a group led by Dieter Seebach in Zurich, Switzerland. See, for example, Seebach et al. (1996)
Helv. Chim. Acta
. 79:913-941; and Seebach et al. (1996)
Helv. Chim. Acta
. 79:2043-2066. In the first of these two papers Seebach et al. describe the synthesis and characterization of a &bgr;-hexapeptide, namely (H-&bgr;-HVal-&bgr;-HAla-&bgr;-HLeu)
2
-OH. Interestingly, this paper specifically notes that prior art reports on the structure of &bgr;-peptides have been contradictory and “partially controversial.” In the second paper, Seebach et al. explore the secondary structure of the above-noted &bgr;-hexapeptide and the effects of residue variation on the secondary structure.
Dado and Gellman (1994)
J. Am. Chem. Soc
. 116:1054-1062 describe intramolecular hydrogen bonding in derivatives of &bgr;-alanine and &ggr;-amino butyric acid. This paper postulates that &bgr;-peptides will fold in manners similar to &agr;-amino acid polymers if intramolecular hydrogen bonding between nearest neighbor amide groups on the polymer backbone is not favored.
Suhara et al. (1996)
Tetrahedron Lett
. 37(10):1575-1578 report a polysaccharide analog of a &bgr;-peptide in which D-glycocylamine derivatives are linked to each other via a C-1 &bgr;-carboxylate and a C-2 &agr;-amino group. This class of compounds has been given the trivial name “carbopeptoids.”
Hamuro et al. (1999)
J. Am. Chem. Soc
. 121:12200-12201, describe antibacterial compositions containing &bgr;-peptides having a repeating 3-peptide residue motif. The compounds described are: Fmoc-(&bgr;
3
-HVal-&bgr;
3
-HLys-&bgr;
3
-HLeu)
n
-OH (n=2-4); H-(&bgr;
3
-HVal-&bgr;
3
-HLys-&bgr;
3
-HLeu)
n
-OH (n=2-4); and H-(&bgr;
3
-HLeu-&bgr;
3
-HLys-&bgr;
3
-HLeu)
n
-OH (n=2-6). While these &bgr;-peptides are described as being antibacterial, they are also hemolytic at concentrations near the effective antibacterial concentrations, thus limiting their utility as medicaments.
SUMMARY OF THE INVENTION
The increasing prevalence of pathogenic bacteria that are resistant to common chemotherapies has prompted an intensive search for new antibiotics. Cationic peptides that adopt amphiphilic secondary structures (e.g., magainins) constitute a widespread host defense against microbial invasions, and mimicry of these natural antibiotics led the present inventors on a search for new synthetic antimicrobial agents. Many of the cationic antimicrobial peptides appear to act by disrupting bacterial membranes, a mechanism that may not be conducive to the development of resistance. The subject invention is directed to antimicrobial compositions containing unnatural cationic oligomers that have no known natural counterpart and that display antibiotic activity comparable to that of a magainin derivative against at least four different bacterial species, including two pathogens that are resistant to common antibiotics. The oligomers are constructed from &bgr;-amino acid building blocks rather than the &agr;-amino acid building blocks of conventional peptides. These &bgr;-peptides exhibit lower hemolytic activity than does the magainin derivative, which indicates a favorable selectivity for bacterial cells relative to mammalian cells. Because &bgr;-peptides are not expected to be subject to protease degradation, these results point toward the rational design of a promising new antibiotic class.
Specifically, the present invention is directed to compounds and to antimicrobial compositions containing the compounds, that is, compositions which inhibit the growth of microbes in general and bacteria and fungi in particular, the compositions comprising an antimicrobial-effective amount of a &bgr;-amino acid oligomer or polymer of the formula:
W-(•••-A-B-C-•••)-Z
wherein “•••-A-B-C-•••” represents a &bgr;-amino acid oligomer or polymer chain, each of A, B, C, etc. representing individual residues of the oligomer or polymer chain and the ellipses representing adjacent N-terminal and C-terminal &bgr;-amino acid residues of the same genus, wherein each residue of the oligomer or polymer chain (that is, each A, B, C, etc.) is the same or different and is independently selected from the group consisting of:
wherein X is selected from the group consisting of hydrogen, linear or branched C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, mono- or bicyclic heteroaryl-C
1
-C
6
-alkyl, —(CH
2
)
n+1
—OR, —(CH
2
)
n+1
—SR, —(CH
2
)
n+1
—S(═O)—CH
2
—R, —(CH
2
)
n+1
—S(═O)
2
—CH
2
—R, —(CH
2
)
n+1
—NRR, —(CH
2
)
n+1
—NHC(═O)R, —(CH
2
)
n+1
—NHS(═O)
2
—CH
2
—R, —(CH
2
)
n+1
—O—(CH)
m
—R
1
, —(CH
2
)
n+1
—S—(CH
2
)
m
—R
1
, —(CH
2
)
n+1
—S(═O)—(CH
2
)
m
—R
1
, —(CH
2
)
n+1
—S(═O)
2
—(CH
2
)
m
—R
1
, —(CH
2
)
n+1
—NH—(CH
2
)
m
—R
1
, —(CH
2
)
n+1
—N—{(CH
2
)
m
—R
1
}
2
, —(CH
2
)
n+1
—NHC(═O)—(CH
2
)
n+1
—R
1
, and —(CH
2
)
n+1
—NHS(═O)
2
—(CH
2
)
m
—R
1
;
wherein R is independently selected from the group consisting of hydrogen, C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteraryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C
1
-C
6
-alkyl, mono- or bicyclic heteroaryl-C
1
-C
6
-alkyl; and
wherein R
1
is selected from the group consisting of hydroxy, C
1
-C
6
-alkyloxy, aryloxy, heteroaryloxy, thio, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylsulfinyl, C
1
-C
6
-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C
1
-C
6
-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C
1
-C
6
-alkylamino, carboxylic acid, carboxamide, mono- or di-C
1
-C
6
-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C
1
-C
6
-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C
1
-C
6
-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane;
wherein Y is selected from the group consisting of hydrogen, linear or branched C
1
-C
6
-alkyl, alkenyl, or alkynyl; mono- or bicycl
Gellman Samuel Helmer
Porter Emilie Ann
Wang Xifang
Weisblum Bernard
Baker Maurie Garcia
DeWitt Ross & Stevens S.C.
Leone, Esq. Joseph T.
Wisconsin Alumni Research Foundation
LandOfFree
Antimicrobial compositions containing &bgr;-amino acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antimicrobial compositions containing &bgr;-amino acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antimicrobial compositions containing &bgr;-amino acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3223358