Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-30
2003-09-02
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C530S317000, C424S405000
Reexamination Certificate
active
06613738
ABSTRACT:
TECHNICAL FIELD
The present invention is related to the isolation of an antimycotic compound. The present invention is also related to an antimycotic composition comprising the compound, and a method for controlling or treating fungal infection, particularly in humans and plants.
BACKGROUND ART
Human and plant infections caused by pathogenic fungi are a continuing and serious problem. Thus, the discovery and characterization of novel, effective antimycotics is especially important. In the case of humans, the increase in fungal infections has resulted, in part, from the frequent use of antibacterial compounds, which enhances opportunities for fungal infections. Furthermore, there is a worldwide increase in the number of immunocompromised patients who are susceptible to fungal infections. This patient population has resulted from the AIDS epidemic, chemotherapy of cancer patients, and the profusion of organ transplant patients (Miller et al., 1998).
Cryptosporiopsis
cf.
quercina
is the imperfect stage of
Pezicula cinnamomea,
a fungus commonly associated with hardwood species in Europe (Sutton, 1980). This fungus and related species occur as endophytes and plant pathogens in many parts of the world (Sutton, 1980). Certain Pezicula spp. and
Zalerion arboricola
produce one or more members of a family of antimycotics, (lipopeptides) known as the pneumocandins. Related lipopeptides, the echinocandins, are also produced by Aspergillus species.
A fungus taxonomically related to
C.
cf
quercina
was isolated as an endophyte from
Tripterigeum wilfordii,
a medicinal plant belonging to the family Celastraceae that is native to Eurasia. Extracts of the culture medium of this fungus demonstrated excellent antifungal activity, especially to
Candida albicans
and Trichophyton spp.
DISCLOSURE OF THE INVENTION
The present application provides spectroscopic, chemical, structural, and biological evidence for the existence of a potent new antifungal agent, Cryptocandin, produced in cultures of
C.
cf
quercina.
The bioactivity of this agent indicates that it would be useful clinically for the treatment of a variety of mycoses.
The new antimycotic, Cryptocandin, appears to be another member of the growing family of aromatic lipopeptide antifungal agents having such important members as echinocandin and pneumocandin whose chemical derivatives are already in advanced human trials. Cryptocandin is indicative of a therapeutic agent as given by its impressive MIC values against
C. albicans
and
H. capsulatum
(Table 5). However, given the MIC values against Trichophyton spp. with only the mini prep C-18 Cryptocandin, it is seen that this compound has enormous potential for the control of skin and nail diseases in humans caused by Trichophyton spp. (Table 4). The results, using Cryptocandin on nail and skin infections with human volunteers have shown promising results.
Structurally, Cryptocandin has the unique aspect of having several amino acids possessing two hydroxy functionalities, and glutamine bearing none (FIG.
5
), whereas pneumocandin and echinocandin have each amino acid hydroxylated (Walsh 1992). It may also be the case that other Cryptocandins occur that differ from each other by virtue of the lipid side chain. This is also a feature with other bioactive bacterially-derived lipopeptide antimycotics (Miller et al., 1998; Ballio et al., 1994).
Given the general antimycotic activity of Cryptocandin and the endophytic nature of
C.
cf
quercina,
if cryptocandin is produced in the plant, it may provide protection to the plant from invading pathogens (Table 6). This may happen at an extremely localized cellular level given how sparse endophytes can tend to be relative to the large number of cells in the plant.
As used herein, the term “Cryptocandin” includes antimycotic lipopeptide compounds found in Cryptosporiopsis. Cryptocandin is preferably a circular aromatic lipopeptide containing several amino acid residues. Preferably, the number of amino acid residues is 4 to 10. More preferably, the number of amino amino acid residues is 4 to 8. Most preferably, the number of amino acid residues is six amino acids. Also most preferably, Cryptocandin comprises equimolar amounts of 1,2-dihydroxy-homotyrosine, 4-hydroxy proline, threonine, glutamine, 3-hydroxy-4-hydroxy methyl proline, 4,5-dihydroxy ornithine, and a lipid. The lipid is preferably a fatty acid. It will be recognized that the invention can be practiced with a Cryptocandin that has been derivatized with any compound so long as the Cryptocandin maintains antimycotic properties.
As for the amino acid content of the lipopeptide of the invention, various ways of classifying the amino acids on the basis of their side groups have been proposed. The most meaningful is based on their polarity. There are four main classes of amino acids: those with (1) nonpolar or hydrophobic side groups, (2) neutral (uncharged) polar side groups, (3) positively charged side groups, and (4) negatively charged side groups (at pH 6.0 to 7.0, the zone of intracellular pH) (Lehninger,
Biochemistry,
1982).
The six amino acid-membered Cryptocandin of the invention includes a lipopeptide described by Formula I, in which position 1 (X
1
) can be any amino acid or its derivative, but preferably has an uncharged polar side group, and more preferably is glutamine or a derivative of glutamine, and most preferably, the glutamine is not hydroxylated. Position 2 (X
2
) can be filled with any amino acid, but is preferably, an amino acid having a nonpolar hydrophobic side group, more preferably, a proline or a derivative of proline, and is most preferably, 3-hydroxy-4-hydroxy methyl-proline. Position 3 (X
3
) can be filled with any amino acid or its derivative, but is preferably, an amino acid with positively charged basic side groups, more preferably, it is ornithine or its derivative, and most preferably, it is 4,5-dihydroxy ornithine. Position 4 (X
4
) can be filled with any amino acid or its derivative, but is preferably an amino acid with uncharged polar side groups, more preferably, it is threonine or its derivative. Position 5 (X
5
) can be filled with any amino acid or its derivative, but is preferably, an amino acid having a nonpolar hydrophobic side group, more preferably, it is proline or its derivative, and most preferably, it is 4-hydroxy-proline. Position 6 (X
6
) can be filled with any amino acid or its derivative, but it is preferably, an amino acid with uncharged polar side groups, more preferably it is tyrosine, most preferably, it is 3,4-dihydroxy-homotyrosine. The “R” group in Formula I can be a lipid, or preferably, fatty acid.
As used herein, “derivatives” of the amino acids include any chemical modification, and preferably, but not limited to hydroxylation.
As used herein, “lipids” include fats and fat-derived materials, including, but not limited to, fatty acid esters, fatty alcohols, sterols and waxes, so long as they can be linked to the lipopeptide of the invention.
As used herein, “fatty acids” include saturated and unsaturated carboxylic acid derived from or contained in an animal or vegetable fat or oil. The fatty acids of the invention are composed of a chain of alkyl groups containing at least 4 carbon atoms, preferably up to 22 carbon atoms. Preferably, the fatty acid is palmitic acid.
Saturated fatty acids include, but are not limited to, butyric (C
4
), lauric (C
12
), myristic (C
14
), palmitic (C
16
), and stearic (C
18
) and all of their hydroxylated derivatives. Unsaturated fatty acids include, but are not limited to, oleic, linoleic, and linolenic (all C
18
).
The fatty acid can be inserted anywhere in the cyclic aromatic lipopeptide. Preferably, the fatty acid is bound to the amino acid at the third position. More preferably, the fatty acid is bound to a nitrogen atom. Most preferably, the fatty acid is bound to the nitrogen atom of a side group.
It will be recognized that the Cryptocandin compound of the present invention can be mixed, bound or associated with any other compound or composition or carrier to form a pharmaceu
HMV Corporation
McDermott & Will & Emery
Tate Christopher R.
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