Peptide antibiotics

Details Peptide antibiotics Peptide antibiotics

2001-02-26

2004-08-31

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

11 to 14 amino acid residues in defined sequence

C530S324000, C530S325000, C530S326000, C514S012200, C514S013800, C514S014800

Reexamination Certificate

active

06784283

ABSTRACT:

TECHNICAL FIELD
The present invention relates to cationic peptides having antibiotic activity.
BACKGROUND OF THE INVENTION
Methicillin-resistant strains of
Staphylococcus aureus
(MRSA) cause infections that are refractory to standard anti-staphylococci antibiotics, and in many cases vancomycin is the antibiotic of last resort. Consequently, it is of great concern that vancomycin-resistant strains of MRSA may develop.
Infections due to enterococci have been difficult to treat for many years because these organisms are intrinsically resistant to many antibiotics. Ampicillin has been the mainstay for treatment of uncomplicated enterococcal infections, but many strains have now become resistant to ampicillin. vancomycin is again the only effective treatment for these ampicillin-resistant enterococcal infections. In the past few years, vancomycin-resistant enterococcal strains(VRE) have begun to appear and they are rapidly spreading across North America. There are no effective antibiotics currently available for such organisms and the recent report of an outbreak of VRE with a 73% mortality rate has highlighted the seriousness of the situation, See Edmond, M. B. et al., Clinical Infections Diseases 20: 1126-33, 1995.
New compounds are needed for the treatment of antibiotic-resistant pathogens, particularly gram positive strains of human pathogens. The present invention is directed to fulfilling this need, and provides related advantages as described herein.
SUMMARY OF THE INVENTION
This invention provides an antibiotic peptide of formula (1):
wherein:
a, b, and c are independently selected integers, wherein a=1-10, b=1−10, and c=2-5;
Y is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms;
LPAA is an amino acid residue having the structure —NX—C
&agr;
R
1
—CO—, wherein for each LPAA in the peptide, R
1
is independently selected from the group consisting of: hydrogen; a linear, branched or cyclic, saturated or unsaturated alkyl containing one to ten carbons atoms optionally substituted with —OH, —OR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F —CN, —O
2
CR, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR, —SOR, or —SO
2
R; benzyl, in which a phenyl ring of the benzyl is optionally substituted with R, —OH, —OR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR —NO
2
, —SOR, or —SO
2
R; and, arylalkyl in which an alkyl group of the arylalkyl has two to ten carbon atoms and is linear, branched or cyclic, saturated or unsaturated, optionally substituted with —OH, —OR, —O
2
CR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR —NO
2
, —SOR, or —SO
2
R, and in which an aryl ring of the arylalkyl is phenyl, or indole, optionally substituted with R, —OH, —OR, —O
2
CR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl —CN, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR —NO
2
, —SOR, or —SO
2
R; wherein for R
1
. R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms, and providing that when R
1
is joined to C
&agr;
by a single bond, H is also present joined to C
&agr;
; and, for each LPAA in the peptide, X is independently selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons;
BAA is an amino acid residue having the structure —NX—CHR
2
—CO—, wherein for each BAA in the peptide, R
2
is independently selected from the group consisting of: a linear, branched or cyclic, saturated or unsaturated alkyl group of one to ten carbons, substituted with one of NH
2
, NRH, NR
2
, NR
3
+
, guanidinyl (—NH—CNH—NH
2
), and imidazole, and optionally substituted with —OH, —OR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —O
2
CR, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR, —SOR, or —SO
2
R; benzyl in which a phenyl ring of the benzyl is substituted with one of NH
2
, NRH, NR
2
, NR
3
+
, and optionally substituted with R, —OH, —OR, —O
2
CR, —SH, —SR, —SOCR, NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR —NO
2
, —SOR, or —SO
2
R; arylalkyl in which an alkyl of the arylalkyl is linear, branched or cyclic, saturated or unsaturated of two to ten carbons, optionally substituted with —OH, —OR, —O
2
CR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —COR, —CONH
2
—CONHR, —CON
2
, —COSR, —NO
2
, —SOR, or —SO
2
R, and in which an aryl ring of the arylalkyl is phenyl substituted with one of NH
2
, NRH, NR
2
, NR
+
, indole substituted with one of NH
2
, NRH, NR
2
, NR
3
+
, pyridine, or imidazole; and wherein the aryl ring is optionally substituted with R, —OH, —OR, —O
2
CR, —SH, —SR, —SOCR, —NHCOR, —I, —Br, —Cl, —F, —CN, —CO
2
R, —CHO, —COR, —CONH
2
, —CONHR, —CONR
2
, —COSR —NO
2
, —SOR, or —SO
2
R; wherein for R
2
, R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms; and, for each BAA in the peptide X is independently selected from the group consisting of: H; OH; and a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbons; and,
R
3
and R
4
=R
1
, and R
3
and R
4
are the same or different.
The term LPAA denotes an amino acid residue having a lipophilic character as compared to BAA. For example, LPAA includes the amino acids glycine, alanine, valine, butyrine, leucine, isoleucine, asparagine, glutamine, tryptophan, tyrosine, phenylalanine, methionine, methionine sulfoxide, threonine, serine, cysteine, and the &agr;,&bgr;-unsaturated analogs of these amino acids except glycine. The term BAA denotes an amino acid residue having a basic character as compared to LPAA. For example, BAA includes the amino acids ornithine, lysine, histidine, and arginine.
The peptide of formula (1) has an N-terminus modified by the presence of an alpha hydroxy acyl group, and a C-terminus reduced to a primary alcohol. R
3
at the N-terminus may be an alkyl group such as —CH(CH
3
)CH
2
CH
3
as is the case for Bogorol A-D as disclosed herein. At the C-terminus, Y in formula (1) may be hydrogen and R
4
may be —CH(CH
3
)
2
, as is the case for Bogorol A-D described herein.
The values of each a, b, and c integer in formula (1) are independently selected The structure of each BAA or LPAA in the peptide may be the same or different as compared to any other BAA or LPAA in the peptide. The number of LPAA components may differ as between different regions along the linear structure of the peptide. Thus, each-[-BAA-(-LPAA)
b
-]-unit of the peptide may have a different BAA residue, different value for b, and different LPAA residues, as compared to any other such unit.
A peptide of formula (1) preferably will have from 10-25 LPAA and BAA residues combined, more preferably from 10-20 and even more preferably from 12-18, which numbers do not include the C-terminal modified amino acid residue Preferably, the number of BAA residues (denoted by the integer c), will be 2-3. Bogorol A-D have a total of 12 LPAA and BAA residues combined, which when added to the modified C-terminal residue, results in a total of 13 amino acid and modified amino acid residues, including 3 BAA residues. Preferably the integer b will be 2-6, more preferably 2-4, and most preferably 2-3. Each BAA residue is preferably separated by from 2-4 and more preferably 2-3 LPAA residues, which means that the integer b is 2-4 or 2-3, but not necessarily at the C-terminus of the peptide. Preferably, the number of LPAA residues at each of the N and C termini of the peptide will be 1-5, more preferably 1-3 and most preferably, 2.
Peptides of this invention may be ordered such that a basic side group of each BAA is aligned along an axis parallel to a central axis of the peptide when the peptide is in an &agr;-helix configuration. This ordering may be achieved by spacing each BAA residue according to the number of residues in each turn of such a helix and providing a

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