CN1798570A

CN1798570A - Anti-fungal compounds and methods of use

Info

Publication number: CN1798570A
Application number: CN 200480014915
Authority: CN
Inventors: 河边拓己; 小林荣孝
Original assignee: Canbas Co Ltd
Current assignee: Canbas Co Ltd
Priority date: 2003-04-07
Filing date: 2004-04-07
Publication date: 2006-07-05
Also published as: ZA200508094B

Abstract

The invention relates to compounds including peptides and peptidomimetics having anti-fungal activity alone, and in combination with other agents that have anti-fungal activity. The invention includes the use of cell cycle G2 checkpoint abrogators as anti-fungal agents, such as anti-fungal medicine.

Description

Anti-fungal compounds and methods of use

Related application

The application requires the priority of the application serial no 60/461,109 of submission on April 7th, 2003, and latter's application is attached to herein by reference.

Technical field

The present invention relates to comprise the chemical compound that itself has antifungal activity of peptide and peptide mimics, and described chemical compound and the combination with other medicaments of antifungal activity.The present invention includes of the application of cell cycle G2 outpost of the tax office remover as antifungal such as antifungal drug.

Technical background

Cell cycle comprises S phase (dna replication dna), M phase (mitosis) and S phase and M two intervals (G1 phase and G2 phase) between the phase.The outpost of the tax office in the cell cycle guarantee process accurately, as the duplicating of the intact condition of monitoring DNA, DNA, the size of cell and environment (Maller, J.L.Curr.Opin.Cell Biol., 3:26 (1991)) on every side.Keep genomic integrity particular importance for multicellular organisms, have the multiple outpost of the tax office can monitor genomic situation, wherein have to appear at before the dna replication dna respectively and the G1 outpost of the tax office and the G2 outpost of the tax office before the mitosis.For multicellular organisms, it is crucial entering and correcting DNA damage before the S phase, in case because damaged dna is replicated, can undergo mutation usually (Hartwell, L.Cell, 71:543 (1992)).Do not repair a large amount of DNA damage and just can cause apoptosis and/or sudden change by the G1 outpost of the tax office and the G2 outpost of the tax office.

The G1 outpost of the tax office associated protein of most of cancerous cell such as p53, Rb, MDM-2, p16 ^INK4And p19 ^ARFUnusual (Levine, A.J.Cell, 88:323 (1997)) takes place.The elimination at the G1 outpost of the tax office causes mutation rate to raise, and appears at observed many sudden changes in the cancerous cell.As a result, most of cancerous cell will rely on the G2 outpost of the tax office and keep out excessive DNA damage survive (O ' Connor and Fan, Prog.Cell Cycle Res., 2:165 (1996)).This situation with do not have the strict cell cycle G1 outpost of the tax office but the unicellular organism body at the strict G2 outpost of the tax office is arranged such as yeast and Mycophyta seemingly.The unicellular organism body is as long as there is an energy to conform to change and just can be survived as species by obtaining favourable sudden change in the middle of them.It helps obtaining useful sudden change at the low stringency in the G1 outpost of the tax office of DNA damage especially.

Now think, cause that the mechanism that cell cycle G2 pauses after the DNA damage all guards in the species from the yeast to the mankind.When having damaged dna, Cdc2/ cell periodic protein B kinases remains on inactivated state, and this is owing to the threonine-14 on the Cdc2 kinases and the inhibition phosphorylation of tyrosine-15 residue, perhaps because the reduction of the protein level of cell periodic protein B.When mitosis began, dual phosphatase Cdc25 removed inhibitory removal phosphoric acid, thereby activated Cdc2/ cell periodic protein B kinases.The activation of Cdc2/ cell periodic protein B equals the beginning of M phase.

In fission yeast, the cell cycle of corresponding damaged dna pauses needs Protein kinase C hk1.The Chk1 zymogenesis can be by phosphorylation modification when DNA damage takes place in several rad gene outcomes downstream of (comprising rad3 (people ATM directly to congener)).The DNA conducted signal that the Rad53 kinases of known budding yeast and the Cds1 kinases of fission yeast can never duplicate.As if there is certain Feng Yuxing between Chk1 and the Cds1, can finally causes pausing and interrupt by the inductive G2 of damaged dna because remove Chk1 and Cds1 simultaneously.Chk1 and Cds1 all can make the Cdc25 phosphorylation, promote combining of rad24 (people 14-3-3 directly to congener) and Cdc25, and this can make Cdc25 and kytoplasm completely cut off, and prevents that the Cdc2/ cell periodic protein B from activating.Seemingly above-mentioned these the kinase whose targets of Cdc25.

Summary of the invention

The invention provides antifungal compound, comprise peptide and peptide mimics, the method for using antifungal compound also is provided.Antifungal compound of the present invention can be used for handling fungus (for example killing or suppress the growth of yeast, mycete, slime mould).This chemical compound can be used to treat any object or the organism that has bad fungus contact, pollutes, grows, breeds or infect or have above-mentioned risk.For example, described chemical compound can be used to treat has object conk or infection or that have this risk, comprises the mammal such as the mankind.

The compounds of this invention can be united use with other treatment or medicament, comprises antifungal therapy and other treatment method.The concrete limiting examples of antifungal therapy comprises for example antifungal or nucleic acid damaging treatment.The available compositions that comprises the present composition and antifungal reduces, reduces or suppresses the contacting of fungus, pollution, growth, propagation or infection.Therefore, the method that can illustrate by this paper is used The compounds of this invention separately or itself and other antifungal therapy is united use.

Therefore the present invention provides the method that suppresses or reduce fungal infection or conk.In one embodiment, described method comprises that the object that makes fungus or contact with fungus contacts with the peptide or the peptide mimics sequence that present in an amount at least sufficient to suppress or reduce fungal infection or conk.

The present invention further provides the method that suppresses or reduce the fungal contamination of object or organism.In one embodiment, described method comprises described object or organism is contacted with the chemical compound that presents in an amount at least sufficient to suppress or reduce the object fungal contamination (comprising peptide or peptide mimics sequence).

The present invention also provides the method for treatment conk or fungal infection.In one embodiment, described method comprises the influence with conk or fungal infection or exists the object of this risk to present in an amount at least sufficient to treat the chemical compound of conk or fungal infection, comprises peptide or peptide mimics sequence.

The present invention provides treatment to have conk, pollution or infection in addition or has the method for conk, pollution or infection in plant, plant part or the seed of this risk.In one embodiment, described method comprise make have conk, pollution or infection or exist plant, plant part or the seed of this risk to contact with the chemical compound that presents in an amount at least sufficient to treat conk, pollution or infection (comprising peptide or peptide mimics sequence).

Peptide of the present invention and peptide mimics sequence comprise with P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, the defined sequence of P2, P1 and have 90% or higher conforming sequence; Wherein P1 is d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), have any aminoacid of one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group in d-or l-(Phe-4CF3), the aminoacid that has similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain; P2 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe ₄NO ₂, have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in the aminoacid in similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical (example at P4 place is d-or l-Trp); P6 is d-or l-Bpa, d-or l-Phe ₄NO ₂, any aminoacid and d-or l-Tyr (for example d-Ser-d-Tyr), any aminoacid and d-or l-Phe (for example d-Ser-d-Phe), any aminoacid or do not exist.

Peptide of the present invention and peptide mimics sequence further comprise with P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, the defined sequence of P2, P1 and have 90% or higher conforming sequence; Wherein P1 is d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), have any aminoacid of one or two aryl, piperidines, piperazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group in d-or l-(Phe-4CF3), the aminoacid that has similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain; P2 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe ₄NO ₂, have have one or two aryl, piperidines, piperazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in the aminoacid in similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical (example at P4 place is d-or l-Trp); P6 is d-or l-Bpa, d-or l-Phe ₄NO ₂, any aminoacid and d-or l-Tyr (for example d-Ser-d-Tyr), any aminoacid and d-or l-Phe (for example d-Ser-d-Phe), any aminoacid or do not exist.

In all fields, the aminoacid with simple carbochain is the amino hendecanoic acid of d-or l-11-, d-or l-10-amino capric acid, d-or l-9-amino-nonanoic acid, d-or l-8-aminocaprylic acid, d-or l-7-aminoheptylic acid, d-or l-6-aminocaproic acid or the similar structures with one or more unsaturated carbon bonds.

Each side of the present invention comprises the compositions of peptide and peptide mimics and antifungal therapy or antifungal.In one aspect, antifungal therapy or antifungal are nucleic acid damaging agents or nucleic acid damaging treatment.Specifically, peptide or peptide mimics can combine with nucleic acid damaging agents, nucleic acid damaging treatment, antifungal or antifungal therapy, to give or to pass to object or other biological body or object.

Other each side of the present invention comprises the compositions of peptide and peptide mimics and antiinflammatory and antimicrobial therapy or antimicrobial.Specifically, peptide or peptide mimics can combine with antiinflammatory or antimicrobial therapy or antiinflammatory or antimicrobial, to give or to pass to object or other biological body or object.

Medicament and treatment comprise medicine, for example chemotherapeutics or have antifungal activity or the medicine of antifungal function.Described medicament and treatment comprise systemic medication and regionality or locality medicine.

The instantiation of medicine comprises the medicine that belongs to following chemical substance classification: allylamine, pyrroles, polyenoid, pyrimidine, tetraene, thiocarbamate, sulfonamide, glucosan synthetic inhibitor and benzoic acid compounds.The instantiation of this medicine comprises: amrolfine, butenafine, naftifine, terbinafine, ketoconazole, fluconazol, elubiol, econazole, econaxole, itraconazole, isoconazole, imidazoles, miconazole, sulconazole, clotrimazole, enilconazole, oxiconazole, tioconazole, terconazole (triaconazole), butoconazole, thiabendazole, voriconazole, Saperconazole, Sertaconazole, fenticonazole, posaconazole, bifonazole, flutrimazole, nystatin, natamycin, amphotericin B, flucytosine, natamycin, tolnaftate, mafenide, dapsone, Caspofungin, actofunicone, griseofulvin, potassium iodide, Gentian Violet, ciclopirox, ciclopirox olamine, haloprogin, undecylenate salt, silver sulfadiazine, undecylenic acid, the undecylenic acid alkanolamide, carbolfuchsin and their prodrug.The other example of this medicine comprises: 5-fluorouracil (5-FU), rebecca mycin, amycin (ADR), bleomycin (Bleo), peplomycin, cis-platinum derivative, camptothecine (CPT) and their prodrug.

Fungus can be present in object or organism, as inside or the surface of human subjects or plant.Described object can be inorganic material or organic material.Described fungus or object can be present in the environment, in residential area, shopping centre, industrial occupancy or the community, perhaps in agricultural or the gardening zone.Described organism can be unicellular organism or multicellular organism.Described cell can be cultured cell or cells in vivo or earlier external back cells in vivo.

Described fungus comprises yeast, mycete or slime mould.Concrete Saccharomyces comprises candidiasis (Canida) and yeast (Saccharomyces).Concrete yeast comprises dermatophytes, Blastomyces coccidioides (Coccidioides immitis), Histoplasma capsulatum (Histoplasmacapsulatum), Candida albicans (Candida albicans) and Aspergillus fumigatus (Aspergillusfumigatus).

Conk or fungal infection can come across the surface of object.The zone of conk, infection, contact or pollution comprises for example skin, toe, fingernail, hair or mucous membrane tissue.Be subjected to the example of the mucous membrane tissue of conk, pollution or infection to comprise for example gastrointestinal tract, oral cavity, lung, bronchial, nasal meatus and nasal sinuses, urogenital tract and vagina.

The present composition and method can be used in part, zone or general.Before the present composition can contact, pollute, grow or infects fungus, basically simultaneously or give afterwards.The present composition can be applied to skin, toe, fingernail, hair or mucous membrane tissue.

Conk or fungal infection can cause various diseases or symptom.Concrete example comprises tinea unguium, tinea cruris or tinea pedis, paracoccidioidomycosis, blastomycosis, mucormycosis, cryptococcosis, coccidioidomycosis, histoplasmosis, candidiasis and aspergillosis.

The present composition and Therapeutic Method can reduce, reduce or suppress fungi growth, pollution, existence or infection.The present composition and Therapeutic Method can reduce the susceptibility of conk, pollution or infection or retransmission rate.The present composition and Therapeutic Method can suppress the deterioration or the development of conk, pollution or infection.

The present composition and method can make by the disease of treatment target and take a turn for the better.Improvement for example can comprise reduce stimulate, itch, inflammation, inflammation, urticaria, serosity are oozed out, pruritus, ejection are excessive, variable color, headache and fatigue; Reduce the susceptibility or the retransmission rate of conk or infection; Suppress the deterioration or the development of object disease.

When plant, plant part or seed were implemented treatment, described contact can be part, zone or system and carries out.Before the treatment that plant, plant part or seed are implemented is included in conk, pollution or infects, basically simultaneously or contact with described sequence afterwards.Plant, plant part or seed can be present in the environment, in industrial occupancy, community, residential area or the shopping centre, perhaps in agricultural or the gardening zone.

Conk, the example that pollutes or infect comprises melasma, anthrax (glomerella), ripe spot, sooty mould, the septoria musiva leaf spot, Cercospora leaf spot, rust, downy mildew, brown rot, brown spot, smut, Verrucosis (Verrucosis), dead arm disease (dead arm disease), ball chamber bacterium (mycosphaerella) leaf spot, the Flos Rosae Rugosae melasma, flower gangrenosis (flower blight), septoria musiva dead leaf disease (septoria leaf blight), early blight and late blight, leaf mold, anthrax, ring spot, dollar spot, the leaf blight of corn, pears alternaria and leaspora spot.

Be used for plant, trees, shrub etc., the instantiation that can be attached to or be applied to the medicine of the present composition and method and treatment comprises that yellow grand, the Mancozeb of Banner Maxx, Compass Cleary ' s, triforine, Immunox, zineb, sulphur ammonia, nitrile bacterium azoles, holder pounce on clean (Topsin), captan, thiram, carboxin, metalaxyl (mefenoxan), PCNB, CGA-173506, thiabendazole, cuprio antifungal, sulfur-containing compound, citrus oils (citrus oils) and bacillus subtilis (Bacillus subtilis).

The present invention provides the method for identifying or screening the chemical compound (for example peptide and peptide mimics) with antifungal activity in addition.In one embodiment, described method comprises that the chemical compound that makes elimination or suppress the G2 outpost of the tax office contacts with fungus; Fungus is cultivated with described chemical compound; With existence, growth or the propagation of measuring fungus.The existence of fungus when chemical compound exists, growth or propagation reduce this chemical compound of confirmation and have antifungal activity.In another embodiment, described method comprises that the chemical compound that makes elimination or suppress the G2 outpost of the tax office contacts with fungus; Fungus is cultivated with described chemical compound; With existence, growth or the propagation of measuring fungus.

Description of drawings

Fig. 1 shows that CBP501 suppresses active to the external phosphorylation of various serine-threonine kinases.Y-axis represents to specify the phosphorylation of kinases to substrate.The 100%th, the kinase activity during no chemical compound.

Fig. 2 shows the antifungal activity of CBP501 when existing and not having the antifungal amphotericin B.

Detailed Description Of The Invention

The invention provides can be used for processing fungi contact, pollute, growth, propagation or infect, and the contact for the treatment of fungi, pollute, growth, propagation or infect relevant or the disease that causes or the compound of illness. Therefore the invention provides the compound with antifungal activity or anti-fungus function that comprises peptide and peptide mimics; And use described compound treatment, minimizing or fungi known contact, pollute, growth, propagation or infect, perhaps reduce or reduce the fungi contact, pollute, growth, propagation or the neurological susceptibility that infects or the method for retransmission rate. Although do not want to be limited by any theory, the compounds of this invention that comprises peptide and peptide mimics suppresses yeast and ability that other fungies contact, pollute, grow, breed or infect and seems at least part of elimination owing to the cell cycle G2 outpost of the tax office.

In one embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), have any amino acid of one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group in d-or l-(Phe-4CF3), the amino acid that has similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain; P2 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles in the amino acid in similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain, any amino acid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P3, P4, P5 are any amino acid, and perhaps one or more among P3, P4, the P5 are simple carbochains, so that the distance of the distance of P2 and P6 when respectively doing for oneself amino acid as P3, P4, P5 is close to identical (example at P4 place is d-or l-Trp); P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, any amino acid and d-or l-Tyr (for example d-Ser-d-Tyr), any amino acid and d-or l-Phe (for example d-Ser-d-Phe), any amino acid or do not exist. In all fields, the amino acid that has a simple carbochain is the amino hendecanoic acid of d-or l-11-, d-or l-10-amino capric acid, d-or l-9-amino-nonanoic acid, d-or l-8-aminocaprylic acid, d-or l-7-aminoheptylic acid, d-or l-6-aminocaproic acid or the similar structures with one or more unsaturated carbon bonds.

In another embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence:

P1, P2, P3, P4, P5, P6; P6, P5, P4, P3, P2, P1; P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12; P1, P2, P3, P4, P5, P6, P12, P11, P10, P9, P8, P7; P6, P5, P4, P3, P2, P1, P7, P8, P9, P10, P11, P12; P6, P5, P4, P3, P2, P1, P12, P11, P10, P9, P8, P7; P7, P8, P9, P10, P11, P12, P1, P2, P3, P4, P5, P6; P7, P8, P9, P10, P11, P12, P6, P5, P4, P3, P2, P1; P12, P11, P10, P9, P8, P7, P1, P2, P3, P4, P5, P6; P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1; P12, P11, P6, P9, P8, P7, P2, P1; P12, P11, P10, P6, P9, P4, P7, P2, P1; P1, P2, P7, P8, P9, P6, P11, P12; Or P1, P2, P7, P4, P9, P6, P10, P11, P12;

Wherein P1 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles in the amino acid in similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain, any amino acid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 is d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), have any amino acid of one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group in d-or l-(Phe-4CF3), the amino acid that has similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain; P3, P4, P5 are any amino acid, and perhaps one or more among P3, P4, the P5 are simple carbochains, so that the distance of the distance of P2 and P6 when respectively doing for oneself amino acid as P3, P4, P5 is close to identical (example at P4 place is d-or l-Trp); P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, any amino acid and d-or l-Tyr (for example d-Ser-d-Tyr), any amino acid and d-or l-Phe (for example d-Ser-d-Phe); Having three among P7, P8, P9, P10, P11, the P12 at least is basic amino acid, and remaining is any amino acid or does not exist. In all fields, the amino acid that has a simple carbochain is the amino hendecanoic acid of d-or l-11-, d-or l-10-amino capric acid, d-or l-9-amino-nonanoic acid, d-or l-8-aminocaprylic acid, d-or l-7-aminoheptylic acid, d-or l-6-aminocaproic acid or the similar structures with one or more unsaturated carbon bonds.

In another embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12; P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1; P12, P11, P10, P6, P9, P4, P7, P2, P1; Or P1, P2, P7, P4, P9, P6, P10, P11, P12; Wherein P1 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles in the amino acid in similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain, any amino acid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 is d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), have any amino acid of one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indoles, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group in d-or l-(Phe-4CF3), the amino acid that has similar side chain space (for example d-or l-Tyr, d-or l-Phe) or the side chain; P3, P4, P5 are any amino acid, and perhaps one or more among P3, P4, the P5 are simple carbochains, so that the distance of the distance of P2 and P6 when respectively doing for oneself amino acid as P3, P4, P5 is close to identical (example at P4 place is d-or l-Trp); P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, any amino acid and d-or l-Tyr (for example d-Ser-d-Tyr), any amino acid and d-or l-Phe (for example d-Ser-d-Phe), any amino acid or do not exist; Having three among P7, P8, P9, P10, P11, the P12 at least is basic amino acid, and remaining is any amino acid or does not exist. In all fields, the amino acid that has a simple carbochain is the amino hendecanoic acid of d-or l-or d-or l-8-aminocaprylic acid.

In a further embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, d-or l-Tyr or d-or l-Phe; P2 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, d-or l-Tyr or d-or l-Phe; P3 is d-or l-serine, d-or l-arginine, d-or l-cysteine, d-or l-proline or d-or l-asparagine; P4 is d-or l-tryptophan; P5 is d-or l-serine, d-or l-arginine or d-or l-asparagine; Perhaps P3, P4, P5 are the amino hendecanoic acid of single d-or l-or single d-or l-8-aminocaprylic acid; P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, (d-Ser-d-Tyr) or (d-Ser-d-Phe).

In a further embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence:

P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12; P1, P2, P3, P4, P5, P6, P12, P11, P10, P9, P8, P7; P6, P5, P4, P3, P2, P1, P7, P8, P9, P10, P11, P12; P6, P5, P4, P3, P2, P1, P12, P11, P10, P9, P8, P7; P7, P8, P9, P10, P11, P12, P1, P2, P3, P4, P5, P6; P7, P8, P9, P10, P11, P12, P6, P5, P4, P3, P2, P1; P12, P11, P10, P9, P8, P7, P1, P2, P3, P4, P5, P6; P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1; P12, P11, P6, P9, P8, P7, P2, P1); P12, P11, P10, P6, P9, P4, P7, P2, P1; P1, P2, P7, P8, P9, P6, P11, P12; Or P1, P2, P7, P4, P9, P6, P10, P11, P12;

Wherein P1 be d-or l-Cha, Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, d-or l-Tyr or d-or l-Phe; P2 be d-or l-Cha, d-or l-Nal (2), d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3), d-or l-Bpa, d-or l-Phe₄NO ₂, d-or l-Tyr or d-or l-Phe; P3 is d-or l-serine, d-or l-arginine, d-or l-cysteine, d-or l-proline or d-or l-asparagine; P4 is d-or l-tryptophan; P5 is d-or l-serine, d-or l-arginine or d-or l-asparagine; Perhaps P3, P4, P5 are the amino hendecanoic acid of single d-or l-or single d-or l-8-aminocaprylic acid; P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, (d-Ser-d-Tyr) or (d-Ser-d-Phe); Have at least three to be d-or l-Arg or d-or l-Lys among P7, P8, P9, P10, P11, the P12, remaining is any amino acid or does not exist.

In a further embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12; P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1; P12, P11, P10, P6, P9, P4, P7, P2, P1; Or P1, P2, P7, P4, P9, P6, P10, P11, P12; Wherein P1 is d-or l-Cha or d-or l-Nal (2); P2 be d-or l-(Phe-2,3,4,5,6-F), d-or l-(Phe-3,4,5F), d-or l-(Phe-4CF3); Have at least three to be d-or l-Arg among P7, P8, P9, P10, P11, the P12, remaining is any amino acid or does not exist; P3 is d-or l-serine; P4 is d-or l-tryptophan; P5 is d-or l-serine or d-or l-asparagine; P6 is d-or l-Bpa, d-or l-Phe₄NO ₂, (d-or l-Ser or d-or l-Tyr) or (d-or l-Ser or d-or l-Phe).

In a further embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or l-Cha or d-or l-Nal (2); P2 be (d-or l-Phe-2,3,4,5,6-F), (d-or l-Phe-3,4,5F) or (d-or l-Phe-4CF3); P3 is d-or l-Ser; P4 is d-or l-Trp; P5 is d-or l-Ser; P6 is d-or l-Bpa or (d-or l-Ser or d-or l-Tyr).

P1，P2，P3，P4，P5，P6；P6， P5，P4，P3，P2，P1；P1，P2，P3，P4，P5，P6，P7，P8，P9，P10，P11，P12；P1，P2，P3，P4，P5，P6， P12，P11，P10，P9，P8，P7；P6，P5，P4，P3，P2，P1，P7，P8，P9，P10，P11，P12；P6，P5，P4，P3， P2，P1，P12，P11，P10，P9，P8，P7；P7，P8，P9，P10，P11，P12，P1，P2，P3，P4，P5，P6；P7，P8， P9，P10，P11，P12，P6，P5，P4，P3，P2，P1；P12，P11，P10，P9，P8，P7，P1，P2，P3，P4，P5，P6； P12，P11，P10，P9，P8，P7，P6，P5，P4，P3，P2，P1；P12，P11，P6，P9，P8，P7，P2，P1；P12，P11， P10，P6，P9，P4，P7，P2，P1；P1，P2，P7，P8，P9，P6，P11，P12；or P1，P2，P7，P4，P9，P6，P10， P11，P12；

Wherein P1 is d-or l-Cha or d-or l-Nal (2); P2 be (d-or l-Phe-2,3,4,5,6-F), (d-or l-Phe-3,4,5F) or (d-or l-Phe-4CF3); P3 is any amino acid (for example d-or l-Ser or d-or l-Pro); P4 is d-or l-Trp; P5 is any amino acid (for example d-or l-Ser); P7 is d-or l-Arg; P8 is d-or l-Arg; P9 is d-or l-Arg; P10 is d-or l-Gln or d-or l-Arg; P11 is d-or l-Arg; P12 is d-or l-Arg; P6 is d-or l-Bpa or (d-or l-Ser or d-or l-Tyr).

In a further embodiment, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12; P12, P11, P10, P9, P8, P7, P6, P5, P4, P3, P2, P1; P12, P11, P10, P6, P9, P4, P7, P2, P1 or P1, P2, P7, P4, P9, P6, P10, P11, P12; Wherein P1 is d-or l-Cha or d-or l-Nal (2); P2 be (d-or l-Phe-2,3,4,5,6-F); P3 is d-or l-Ser; P4 is d-or l-tryptophan; P5 is d-or l-Ser; P7 is d-or l-Arg; P8 is d-or l-Arg; P9 is d-or l-Arg; P10 is d-or l-Gln or d-or l-Arg; P11 is d-or l-Arg; P12 is d-or l-Arg; P6 is d-or l-Bpa or (d-or l-Ser or d-or l-Tyr).

In other embodiments, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence:

(d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha); (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa) (d-Arg) (d-Arg) (d-Gln (d-Arg) is (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Arg) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa); (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Ser) (d-Trp) (d-Ser) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha) of (d-Arg) (d-Arg); (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Phe-2,3,4,5,6-F) (d-Cha); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Trp) (d-Arg) (d-Pbe-2,3,4,5,6-F) (d-Cha); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Trp) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Trp) (d-Arg) (d-Phe-2,3,4,5,6-F) (d-Cha); (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Trp) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg) (d-Arg); (d-Arg) (d-Arg) (d-Arg) (d-BPa) (d-Arg) (d-Arg) (d-Arg) (d-Phe-2,3,4,5,6-F) (d-Cha); Or (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Bpa) (d-Arg) (d-Arg) (d-Arg).

In other embodiments, the compounds of this invention comprise comprise following structure adjoin peptide or peptide mimics sequence: (d-Bpa) (d-Ser) (d-Trp) (d-Ser) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg).

In more embodiment, the compounds of this invention contains following peptide or peptide mimics sequence: the X of adjoining₁X ₂X ₃X ₄X ₅X ₆X ₇X ₈X ₉X ₁₀X ₁₁, X wherein₁Be L, F, W, M, R, I, V, Y, K or do not have X₂Y, F, A, W, S or T, X₃Any amino acid, X₄Any amino acid, X₅Any amino acid, X₆S, A, N, H or P, X₇Any amino acid, X₈Any amino acid, X₉Be any amino acid or do not have X₁₀Be N, G, L, S, M, P, N, A or do not have X₁₁Be L or do not exist. In all fields, X₁Be L, F, W, M, R or do not exist, perhaps X₁L, F or W; X₂Y, F, A; X₃R, T, S, H, D, G, A, L, K, A, N, Q or P, perhaps X₃R, T, S, H, D, G, A or L, perhaps X₃R, T, S or H; X₄S, T, G, A, L, R, I, M, V, P or X₄S, T, G, A, L, R or X₄S; X₅P, A, G, S or T or X₅P; X₆S, N, H, P, A, G or T or X₆S, N or H or X₆S; X₇M, F, Y, D, E, N, Q, H, G, I, L, V, A, P, N or W, perhaps X₇M, F, Y, D, E, N, Q or H, perhaps X₇M, F, Y, Q or H; X₈P, F, Y, W, L, G, M, D, E, N, Q, H, I, V, A or P, perhaps X₈P, F, Y or W, perhaps X₈Y; X₉Be E, G, L, S, M, P, N, D, A, T, P or do not exist; X₁₀Not exist; X₁₁Not exist; In a further embodiment, X₂Y, X₅P, X₁₀N; X₃R, X₈P, X₁₁L; X₄S, X₅P, X₆S, X₉E, X₁₀N, X₁₁L.

In more embodiment, the compounds of this invention contains following peptide or the peptide mimics sequence of adjoining: Y G G P G G G G N (SEQ ID NO:1); R Y S L P P E L S N M (SEQ ID NO:2); L A R S A S M P E A L (SEQ ID NO:3); L Y R S P S M P E N L (SEQ ID NO:4); L Y R S P A M P E N L (SEQ ID NO:5); W Y R S P S F Y E N L (SEQ ID NO:6); W Y R S P S Y Y E N L (SEQ ID NO:7); Or, W Y R S P S Y Y (SEQ ID NO:8).

In other embodiment, the compounds of this invention contains following peptide or the peptide mimics sequence of adjoining:

L Y R S P S Y P E N L(SEQ ID NO：9)，L Y R S P S Y F E N L(SEQ ID NO：10)，L Y R S P S Y Y E N L，(SEQ ID NO：11)，L Y R S P S Y W E N L (SEQ ID NO：12)，L Y R S P S N P E N L(SEQ ID NO：13)，L Y R S P S N F E N L(SEQ ID NO：14)，L Y R S P S N Y E N L(SEQ ID NO：15)，L Y R S P S N W E N L(SEQ ID NO：16)，L Y R S P S H P E N L(SEQ ID NO：17)，L Y R S P S H F E N L(SEQ ID NO： 18)，L Y R S P S H Y E N L(SEQ ID NO：19)，L Y R S P S H W E N L(SEQ ID NO：20)， L Y S S P S M P E N L(SEQ ID NO：21)，L Y S S P S M F E N L(SEQ ID NO：22)，L Y S S P S M Y E N L(SEQ ID NO：23)，L Y S S P S M W E N L(SEQ ID NO：24)，LY S S P S F P E N L(SEQ ID NO：25)，L Y S S P S F P E N L(SEQ ID NO：26)，L Y S S P S F F E N L(SEQ ID NO：27)，L Y S S P S F Y E N L(SEQ ID NO：28)，L Y S S P S F W E N L(SEQ ID NO：29)，L Y S S P S Y P E N L(SEQ ID NO：30)，L Y S S P S Y F E N L(SEQ ID NO： 31)，L Y S S P S Y Y E N L(SEQ ID NO：32)，L Y S S P S Y W E N L(SEQ ID NO：33)，L Y S S P S Q P E N L(SEQ ID NO：34)，L Y S S P S Q W E N L(SEQ ID NO：35)，L Y S S P S H P E N L(SEQ ID NO：36)，L Y S S P S H F E N L(SEQ ID NO：37)，L Y S S P S H Y E N L(SEQ ID NO：38)，L Y S S P S H W E N L(SEQ ID NO：39)，L Y T S P S M P E N L (SEQ ID NO：40)，L Y T S P S M F E N L(SEQ ID NO：41)，L Y T S P S M Y E N L(SEQ ID NO：42)，L Y T S P S M W E N L(SEQ ID NO：43)，L Y T S P S F P E N L(SEQ ID NO：44)，L Y T S P S F F E N L(SEQ ID NO：45)，L Y T S P S F Y E N L(SEQ ID NO： 46)，L Y T S P S F W E N L(SEQ ID NO：47)，L Y T S P S Y P E N L(SEQ ID NO：48)，L Y T S P S Y F E N L(SEQ ID NO：49)，L Y T S P S Y Y E N L(SEQ ID NO：50)，L Y T S P S Y W E N L(SEQ ID NO：51)，L Y T S P S N P E N L(SEQ ID NO：52)，L Y T S P S N F E N L(SEQ ID NO：53)，L Y T S P S N Y E N L(SEQ ID NO：54)，L Y T S P S N W E N L (SEQ ID NO：55)，L Y T S P S H P E N L(SEQ ID NO：56)，L Y T S P S H F E N L(SEQ ID NO：57)，L Y T S P S H Y E N L(SEQ ID NO：58)，L Y T S P S H W E N L(SEQ ID NO：59)，L Y H S P S Y P E N L(SEQ ID NO：60)，L Y H S P S Y F E N L(SEQ ID NO： 61)，L Y H S P S Y Y E N L(SEQ ID NO：62)，L Y H S P S Y W E N L(SEQ ID NO：63)， L F T S P S Y P E N L(SEQ ID NO：64)，L F T S P S Y F EN L(SEQ ID NO：65)，L F T S P S Y Y E N L(SEQ ID NO：66)，L F T S P S Y W E N L(SEQ ID NO：67)，F Y S S P S H P E N L(SEQ ID NO：68)，F Y S S P S H F E N L(SEQ ID NO：69)，F Y S S P S H Y E N L (SEQ ID NO：70)，F Y S S P S H W E N L(SEQ ID NO：71)，F Y T S P S M P E N L(SEQ ID NO：72)，F Y T S P S M F E N L(SEQ ID NO：73)，F Y T S P S M Y E N L(SEQ ID NO：74)，F Y T S P S M W E N L(SEQ ID NO：75)，F Y T S P S F P E N L(SEQ ID NO： 76)，F Y T S P S F F E N L(SEQ ID NO：77)，F Y T S P S F Y E N L(SEQ ID NO：78)，F Y T S P S F W E N L(SEQ ID NO：79)，F Y T S P S Y P E N L(SEQ ID NO：80)，F Y T S P S Y F E N L(SEQ ID NO：81)，F Y T S P S Y Y E N L(SEQ ID NO：82)，F Y T S P S Y W E N L(SEQ ID NO：83)，W Y R S P S M P E N L(SEQ ID NO：84)，W Y R S P S M F E N L(SEQ ID NO：85)，W Y R S P S M Y E N L(SEQ ID NO：86)，W Y R S P S M W E N L (SEQ ID NO：87)，W Y R S P S F P E N L(SEQ ID NO：88)，W Y R S P S F F E N L(SEQ ID NO：89)，W Y R S P S F Y E N L(SEQ ID NO：90)，W Y R S P S F W E N L(SEQ ID NO：91)，W Y R S P S Y P E N L(SEQ ID NO：92)，W Y R S P S Y F E N L(SEQ ID NO： 93)，W Y R S P S Y Y E N L(SEQ ID NO：94)，W Y R S P S Y W E N L(SEQ ID NO：95)， W Y T S P S M P E N L(SEQ ID NO：96)，W Y T S P S M F E N L(SEQ ID NO：97)，W Y T S P S M Y E N L(SEQ ID NO：98)，W Y T S P S M W E N L(SEQ ID NO：99)，W Y T S P S F P E N L(SEQ ID NO：100)，W Y T S P S F F E N L(SEQ ID NO：101)，W Y T S P S F Y E N L(SEQ ID NO：102)，W Y T S P S F W E N L(SEQ ID NO：103)，W Y T S P S Y P E N L(SEQ ID NO：104)，W Y T S P S Y F E N L(SEQ ID NO：105)，W Y T S P S Y Y E N L(SEQ ID NO：106)，W Y T S P S Y W E N L(SEQ ID NO：107)，W Y T S P S H P E N L(SEQ ID NO：108)，W Y T S P S H F E N L(SEQ ID NO：109)，W Y T S P S H Y E N L (SEQ ID NO：110)，W Y T S P S H W E N L(SEQ ID NO：111)，L K R S P S M P E N L (SEQ ID NO：112)，L Y I S P S M P E N L(SEQ ID NO：113)L Y R S P S M V E N L (SEQ ID NO：114).

。，TAT，Y G R K K R R Q R R R(SEQ ID NO：115)。

The compounds of this invention comprises prodrug." prodrug " used herein refers in vivo can be by metabolism, transform or be modified into the chemical compound of activity form, and described activity form is as the peptide of peptide mimics with antifungal activity or function.Often use prodrug to be because prodrug may be than the easier administration of parent drug, or compare its bioavailability or dissolubility with parent drug higher.The concrete limiting examples of prodrug is the polypeptide that is connected with peptide of the present invention or peptide mimics by amino or carboxyl end groups.The hydrolysis or by metabolism in vivo of described polypeptide, thus discharge bioactive peptide or peptide mimics.Therefore, The compounds of this invention and method comprise peptide or peptide mimics prodrug, its in vivo by metabolism, transform or be modified into the activity form of peptide or peptide mimics.

The compounds of this invention has antifungal activity or antifungal function, perhaps has G2 elimination or G2 and suppresses active.Term used herein " antifungal activity " and " antifungal function " refer in environment, in agricultural or gardening zone or in shopping centre, industrial occupancy, residential area or community, in the body of external, earlier external back, can detect in the body or measurable reduction, minimizing or suppress the fungus contact, pollute, growth, existence, propagation or infect.As the common kill fungi of the chemical compound of antifungal, and reduce usually or inhibition fungi growth, existence or propagation as the chemical compound of antifungal.

Reduce, reduce or suppress fungus contact, pollution, growth, existence, propagation or infect the amount that can reduce fungal contamination, growth, existence, propagation or infection; Perhaps prevent or inhibition contacts, grows, pollutes, infects or breed relevant acute or chronic sympton, disease or advancing of disease or deterioration with fungus.For example, in animal, one or more fungal infection that can reduce or suppress relevant or by its symptom that causes or disease comprise stimulation, itch, inflammation, inflammation, urticaria, serosity are oozed out, pruritus, ejection are excessive, variable color, headache and fatigue.In environment, perhaps in agricultural, gardening, industry, community, commerce or residential area, reduce or suppress the fungus contact, pollute, growth, existence, propagation or infect can reduce the fungus contact, pollute, the amount of growth or propagation.

Antifungal activity can comprise reduction or reduce the susceptibility that fungus contacts, pollutes, grows, survives, breeds or infects with the antifungal function, or the retransmission rate that reduces or reduce fungus contact, pollution, growth or infect.No matter be in environment or in industry, commercial, live, in community or agricultural or the gardening zone, antifungal activity and antifungal function can come across anyly to be had in life organism or the lifeless object, for example in the mammal such as the mankind or the veterinary's object, perhaps come across and be subject to fungal contamination, in the inorganic or organic material of growth or infection influence, if any life or dead organic substance, biofluid, cell, organ or tissue, perhaps any plant, trees, shrub or gardening or agricultural products (are for example spent, grass, timber, nut, agricultural product, corn etc.) in.

Term used herein " object " refers generally to abiotic or original lived subject.Object can be made up of organic or inorganic material or their combination.No life organism belongs within the implication of term used herein " object ".The object that is subject to the fungus contact, pollutes, grows, breeds or infects influence comprises machinery, instrument, apparatus, device, instrument, equipment (for example being used for food processing), container, packaging material or surface.Described object also comprises the medical material that sees healthcare facility such as clinic and hospital.The object that is subject to fungus contact, pollution, growth, propagation and infection influence further comprises for example cloth, leather, shoes, socks, glove, medicated cap, carpet and woollen blanket, floor, timber, wallboard and house dust.The influence that any thing of being made by organic material all is subject to the fungus contact basically, pollutes, grows, breeds and infect.

Term " fungus " and grammatical variants thereof refer to belong to any organism of mycota.Instantiation comprises yeast, mycete, slime mould, mushroom and lichens.

Term used herein " G2 " and " G2/M " phalangeal cell cycle G2 to M phase outpost of the tax office.The G2 outpost of the tax office in term " G2 elimination " and " G2 inhibition " active phalangeal cell cycle is destroyed, so that cell just enters the M phase without the G2 outpost of the tax office, refers to that perhaps the persistent period of comparing the G2 outpost of the tax office with the time span that cell normally is in G2 shortens.Therefore, for example eliminate or suppress the peptide at the G2 outpost of the tax office or peptide mimics and can quicken G2 to the transition of M phase, this can induce again conversely or irritation cell in that to enter M dead before or after the phase.The chemical compound at the elimination or the inhibition G2 outpost of the tax office refers to that any time span generation that makes cell be in the G2 outpost of the tax office can detect or the chemical compound of measurable minimizing.

Term used herein " peptide ", " polypeptide " and " protein " are used interchangeably, and refer to by amido bond or suitable two or more covalently bound aminoacid of non-amido bond.Peptide of the present invention can be random length.Peptide can have about 5-100 or more residue, is 5-12,12-15,15-18,18-25,25-50,50-75,75-100 or longer as length.Have few peptide activity is arranged to five residues.For example, (Bpa) (X) (Trp) (X) (Trp) (X) (PheF5) (Cha) intimate identical of (X) activity (Bpa) and (Bpa).Peptide of the present invention comprises the combination of l-and d-isomer and l-and d-isomer.Described peptide can comprise the modification of the translation post-treatment of common protein involved, for example cyclisation (for example disulfide bond or amido bond), phosphorylation, glycosylation, carboxylation, ubiquitinization, myristylation or lipidization.

Peptide disclosed herein also comprises having the chemical compound that is similar to amino acid structure and function, the peptide mimics that for example has synthetic or non-natural aminoacid or amino acid analogue, as long as described analogies have one or more functions or activity, for example antifungal activity.Therefore, The compounds of this invention comprises " analogies " and " peptide mimics " form.

Term used herein " analogies " and " peptide mimics " refer to have the synthetic compound with essentially identical structure of peptide of the present invention and/or functional character.Analogies can be made up of synthetic alpha-non-natural amino acid analog fully, perhaps can be the chimeric molecules that comprises one or more native peptides aminoacid and one or more alpha-non-natural amino acid analog.Can sneak into also in the analogies that any amount of natural amino acid is conservative to be replaced, as long as the activity that this replacement can the crash simulation thing.The activity that whether analogies have needs is determined in available routine test, and for example whether it has detectable antifungal activity.When using term " substantially the same " to refer to analogies or peptide mimics, the meaning is one or more activity or the function that analogies or peptide mimics have reference molecule, for example antifungal activity.

The peptide mimics compositions can comprise any combination of non-natural constituent, and described constituent is usually from following three kinds of structured sorts: a) the residue linking group except that natural amido bond (" peptide bond ") connects; B) the non-natural residue of displacement natural amino acid residue; Or c) brings out the mimic residue of secondary structure, promptly bring out or the residue of stable secondary structure such as βZhuan Jiao, γ corner, βZhe Die, alpha helical conformation etc.Polypeptide can be described as analogies when for example, one or more residues connected by the chemical mode outside the amido bond.Each residue of peptide mimics can be connected by amido bond, non-natural and non-amidated key, other chemical bonds or coupling mode, comprise for example glutaraldehyde, N-hydroxy-succinamide ester, difunctionality maleimide, N, N '-dicyclohexylcarbodiimide (DCC) or N, N '-DIC (DIC).Can replace the linking group of amido bond for example comprise the ketone methylene (for example-C (=O)-CH ₂-, replacement-C (=O)-NH-), aminomethylene (CH ₂-NH), ethylene, alkene (CH=CH), ether (CH ₂-O), thioether (CH ₂-S), tetrazolium (CN ₄-), thiazole, retroamide, thioamides or ester (referring to for example Spatola (1983), Chemistry and Biochemistry of Amino Acids, Peptides And Proteins,The 7th volume, the 267-357 page or leaf, " Peptide and BackboneModifications, " Marcel Decker, NY).

As mentioned above, the peptide that is called analogies is characterized by the non-natural residue that contains one or more displacement natural amino acid residues.The non-natural residue is well known in the art.The concrete limiting examples that can be used as the non-natural residue of natural amino acid residue analogies is the analogies of aromatic amino acid, comprises for example D-or L-naphthyl (naphyl) alanine; D-or L-phenylglycine; D-or L-2 thienyl (thieneyl) alanine; D-or L-1 ,-2,3-, or 4-pyrenyl alanine; D-or L-3 thienyl alanine; D-or L-(2-pyridine radicals)-alanine; D-or L-(3-pyridine radicals)-alanine; D-or L-(2-pyrazinyl)-alanine; D-or L-(4-isopropyl)-phenylglycine; D-(trifluoromethyl)-phenylglycine; D-(trifluoromethyl)-phenylalanine; D-is to the fluoro-phenylalanine; D-or L-are to the xenyl phenylalanine; K-or L-are to methoxyl group-xenyl phenylalanine; D-or L-2-indole (alkyl) alanine; With D-or L-alkyl alanine, wherein alkyl can be to replace or unsubstituted methyl, ethyl, propyl group, hexyl, butyl, amyl group, isopropyl, isobutyl group, sec-isotyl, isopentyl, or nonacid aminoacid.The alpha-non-natural amino acid aromatic ring that can be used to replace natural aromatic ring comprises for example thiazolyl, thienyl, pyrazolyl, benzimidazolyl, naphthyl, furyl, pyrrole radicals and pyridine radicals aromatic ring.

The analogies of acidic amino acid can keep negative charge simultaneously again by with non-carboxylic acid amino acid replacement; (phosphino-) alanine; Produce with the sulphation threonine.Carboxyl side group (for example aspartyl or glutamyl) also can by with carbodiimide (R '-N-C-N-R ') reaction carrying out selective modification; carbodiimide comprises for example 1-cyclohexyl-3 (2-morpholinyl-(4-ethyl) carbodiimide or 1-ethyl-3 (4-azo (azonia)-4,4-dimethoxy (dimethol) amyl group) carbodiimide.Asparagyl or glutamyl also can be by being converted into asparaginyl-and glutaminyl with the ammonium ion reaction.

Except that lysine and arginine, the analogies of basic amino acid can produce with amino acid replacements such as ornithine, citrulline or (guanidine radicals) acetic acid or (guanidine radicals) acetate alkyls, wherein alkyl can be to replace or unsubstituted methyl, ethyl, propyl group, hexyl, butyl, amyl group, isopropyl, isobutyl group, sec-isotyl, isopentyl, or nonacid aminoacid.Available carbonitrile derivatives (for example containing the CN-part, displacement COOH) displacement agedoite or glutamine.But asparaginyl-and glutaminyl residue deamination form corresponding aspartyl or glutamyl residue.

The arginine analogies can be chosen wantonly under alkali condition and one or more reagent by making arginyl-, comprise for example phenyl Biformyl, 2,3-diacetyl, 1, and 2-cyclohexanedione or ninhydrin reaction produce.The tyrosine residue analogies can produce by tyrosyl-and aromatics diazonium compound or tetranitromethane are reacted.Can use N-acetyl imidazole and tetranitromethane to form O-acetyl tyrosyl-group and 3-nitro-derivative respectively.

The lysine analogies can produce (and n terminal residue can be changed) by lysyl-and succinic anhydrides or other carboxylic acid anhydrides are reacted.Lysine and other contain alpha-amino residue analogies also can by with imino-ester such as pyridine azomethine acid methyl ester, pyridoxal 5-phosphate, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., hydroboration chlorine, trinitro-benzene-sulfonic acid, O-methyl-isourea, 2, the 4-pentanedione reacts, and produces by transamidase catalysis and glyoxalic acid reaction.

The methionine analogies can produce by reacting with methionine sulfoxide.The proline analogies comprise for example pipecolinic acid, Thiazolidine carboxylic acid, 3-or 4-hydroxyproline, dehydroproline, 3-or 4-methylproline and 3,3 ,-dimethyl proline.The histidine analogies can produce by histidyl-and pyrocarbonic acid diethyl ester or PBPB are reacted.Other analogies comprise the analogies that for example produce by the following method: the hydroxylating of proline and lysine; The phosphorylation of the hydroxyl of seryl-or Threonyl residue; The alpha-amino of lysine, arginine and histidine methylates; The acetylation of N-terminal amine; The methylating or replace of main chain amide residues with the N-methylamino acid; The perhaps amidatioon of C-terminal carboxyl group.

The aminoacid that also available chirality is opposite (or peptide mimics residue) replaces one or more residues.Therefore, any aminoacid with the natural appearance of L-configuration (also can be called R or S configuration, depend on the structure of chemical individual) can replace with chirality opposite same amino acid or analogies (be called D-aminoacid, but also can be called R-or S-configuration in addition).

Peptide of the present invention and peptide mimics also comprise the modified forms of the sequence that this paper proposes, and condition is that described modified forms keeps unmodified or with reference at least a portion function of peptide or peptide mimics.For example, modified peptides or peptide mimics must keep at least a portion antifungal activity, improve or reduce but compare its antifungal activity or G2 elimination activity with reference peptide or peptide mimics.

One or more amino acid residues of modified peptides and peptide mimics can be replaced by another residue, perhaps have one or more amino acid residues to be added in modified peptides and the peptide mimics sequence or lack from sequence.In one embodiment, modified peptides and peptide mimics have one or more amino acid replacements, interpolation or disappearance (for example 1-3,3-5,5-10 or more residue).On the one hand, available its side chain of described displacement has and carries out with reference to the aminoacid or the analogies of aminoacid or analogies (by metathetical aminoacid or analogies) approximation space.On the other hand, carry out with the proximate non-human aminoacid of human amino acid residue on the described displacement possible constructions.One concrete aspect, described displacement is a conservative amino acid replacement.

Term used herein " approximation space " refers to its three dimensions that occupies size and the proximate chemical part of reference section.Usually, it is approximate with reference section to occupy its size of part of approximation space.The three dimensions size that the aminoacid that " occupies approximate side chain space " or its side chain of analogies occupy is with close with reference to aminoacid or analogies.For d-(Phe-2,3,4,5,6-F), l-(Phe-2,3,4,5,6-F), d-(Phe-3,4,5F), l-(Phe-3,4,5F), d-(Phe-4CF3) or l-(Phe-4CF3), instantiation is (l or d-Phe-2R1,3R2,4R3,5R4,6R5), wherein R1, R2, R3, R4, R5 can be chlorine, bromine, fluorine, iodine, hydrogen, hydrogen oxide or not exist.For micromolecule, be about the fluorine of 1 dust as size, proximate space can not exist for part.

Term " conservative substitution " refer to an aminoacid by biologically, chemically or on the structure proximate residue replace.Biologically described displacement of approximate finger and biologic activity such as antifungal activity are compatible.The amino acid whose side chain lengths of approximate finger is approximate on the structure, and as alanine, glycine and serine, or the big side of chain is little approximate.The chemistry approximation refers to that residue has identical electric charge, perhaps is hydrophilic or hydrophobicity.Concrete example comprises with a hydrophobic residue, replace another hydrophobic residue as isoleucine, valine, leucine or methionine, perhaps replace another polar residues, as arginine displacement lysine, glutamic acid displacement aspartic acid or glutamine displacement agedoite, serine displacement threonine etc. with a polar residues.

Therefore, peptide of the present invention and peptide mimics comprise its sequence and table 1 is listed and this paper is given an example peptide and peptide mimics sequence peptide and peptide mimics inequality.In one embodiment, the sequence that proposes of peptide and peptide mimics and this paper has 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or higher concordance.

Peptide of the present invention and peptide mimics comprise essentially identical peptide of sequence and the peptide mimics that proposes with this paper.When referring to peptide and peptide mimics with term " basic identical ", the meaning is that its sequence and reference sequences have at least 75% or higher concordance (for example 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).The length of comparative sequences generally is 5 aminoacid at least, but more usually, reaches 6-10,10-15 or more residue at least.On the one hand, concordance relates to clear and definite sequence area, as 3-5 residue of amino or carboxyl terminal.

The compounds of this invention comprises that peptide and peptide mimics can produce and separate with any method well known in the art.The synthetic peptide of available chemical method well known in the art in whole or in part (referring to for example Caruthers (1980) Nucleic Acids Res.Symp.Ser.215-223; Horn (1980) Nucleic Acids Res.Symp.Ser.225-232; And Banga, A.K., Therapeutic Peptides and Proteins, Formulation, Processing and DeliverySystems (1995) Technomic Publishing Co., Lancaster, PA).The synthetic available various solid phase techniques of peptide carry out (referring to for example Roberge (1995) Science 269:202; Merrifield (1997) Methods Enzymol.289:3-13), can for example use for example ABI 431A peptide synthesizer (Perkin Elmer) realization synthetic automatically by manufacturers instruction.

Available multiple program well known in the art and method (referring to for example Organic SynthesesCollective Volumes, Gilman etc. (editor) John Wiley ﹠amp; Sons, Inc. NY) comes synthetic each synthetic residue and polypeptide that mixes analogies.Peptide and peptide mimics also available combination method synthesize.Technology in order to generation peptide and peptide mimics library is known, comprises that for example much scalp acupuncture technology, Folium Camelliae sinensis packet technology and shearing-coupling-hybrid technology are (referring to for example al-Obeidi (1998) Mol.Bioteclinol.9:205-223; Hruby (1997) Curr.Opin.Chem.Biol.1:114-119; Ostergaard (1997) Mol.Divers.3:17-27; And Ostresh (1996) Methods Enzymol.267:220-234).Modified peptides can further prepare (referring to for example Belousov (1997) Nucleic Acids Res.25:3440-3444 by chemical modification method; Frenkel (1995) Free Radic.Biol.Med.19:373-380; And Blommers (1994) Biochemistry 33:7886-7896).

In The compounds of this invention and compositions can be used for external, the earlier external back body with body in (for example at whole body, zone, part or on mucous membrane tissue) inhibition fungus contact, pollute, grow, survive, breed or infect.Like this, have fungus contact, pollute, growth, existence, propagation or infect or have a this risk any life thing or xenobiotic arranged, perhaps fungus contact, pollute, growth, existence, propagation or infect and cause or relevant infringement or situation that all available The compounds of this invention is handled.

Therefore, the invention provides inhibition, reduce and reduce external, earlier in the body of external back with body in the fungus method that contacts, pollute, grow, survive, breed and infect.This method comprises contacting of inhibition, reduction or minimizing and fungus; Suppress, reduce or minimizing fungi growth or propagation; Suppress, reduce or reduce the infection of fungus; Suppress, reduce or reduce the pollution of fungus; Suppress, reduce or reduce the existence of fungus; With the susceptibility or the retransmission rate that suppress, reduce or minimizing contacts, pollutes, grows, survives, breeds or infect fungus.

In the embodiment, method comprises to be made the contact of life organism or lifeless object (for example any material) present in an amount at least sufficient to reduce, reduce or suppresses fungus at described organism, object or near the The compounds of this invention of contact, pollution, growth, existence, propagation or infection in other objects of this object.On the one hand, described organism is an animal, as mammal (for example people).On the other hand, described object comprises organic or inorganic material (for example construction material or medical material).Aspect another, described object comprises instrument, machinery, unit, instrument, medical material or surface.Aspect other, described object is in the environment various, or in industrial occupancy, residential area, shopping centre, community, agricultural or gardening zone.

Term used herein " object " refer to be subjected to fungus contact or pollute, by fungal infection, perhaps tolerable, support or help the fungus contact, pollute, growth, existence, propagation or any abiotic or original lived subject that infects.Therefore, object comprises any organic or inorganic material that is subject to the fungus contact, pollutes, grows or infect, as the part of abiotic organic substance, biofluid, cell, organ or tissue or original lived organism, as gardening or agricultural products (for example plant, flowers and plants, vegetable, fruit, nut and corn and their part etc.).Organism refers to any life thing that has, for example mammal such as people or veterinary's object, plant, grass, trees, shrub, crops, vegetable, fruit etc.Plant part comprises leaf, stem, root, flower, seed, trunk and branch, because conk, pollution or infection can appear on leaf, stem, root, flower, seed, trunk or the branch to small part.

Object also comprises any apparatus, instrument, device, instrument, machinery, equipment (for example being used for food processing), container, packaging material or surface.Described object can appear in residential area, shopping centre or the community, as comprises the surface that is subject to fungus contact or dwelling house, room, apartment, hotel or motel, hospital or clinic, school, auditorium or the office of material (as timber, fiber or other organic or inorganic materials) or ventilating system.Object can appear at industrial occupancy (for example produce, process, dispensing, preservation or sale of foodstuffs such as cheese, milk or any unprocessed, aged, that cultivate, processing or beverage of fermentation or the zone of food product), for example comprise for example be subject to the fungus contact, pollute, production, processing, preservation or the dispensing building or the facility of growth, existence, propagation or the machinery that infects or equipment or organic substance (for example Foods or drinks).Object can appear in the environment, as farm or pasture, or appears at agricultural or gardening zone (for example greenhouse or nursery), or other harvesting or cultural area.Object also can appear in the natural environment, for example the cutting area.

The present invention further provides the method for handling the fungus contact, polluting, grow, breed or infect, perhaps object by fungus contact, pollute or infect after or before the method for relevant disease in (for example in order to prevent) treatment target, described disease comprises the fungus contact, pollutes, growth, propagation or infect the disease that causes or be correlated with.In the embodiment, this method comprises that its amount of object that has fungal infection or this risk is arranged can effectively treat the The compounds of this invention of fungal infection.On the one hand, described amount is enough to improve the disease of object.In other respects, described improvement comprises the order of severity or persistent period, the minimizing of one or more symptoms that minimizing conk or fungal infection cause or reduces the susceptibility of object to conk or fungal infection, or reduces or reduce the retransmission rate of conk or fungal infection.Aspect another, before giving another kind of treatment of object (as antifungal therapy) or antifungal, simultaneously or afterwards, give the object The compounds of this invention.Other concrete aspect, fungal infection is positioned at skin (for example scalp, oxter, foot, groin), toe or fingernail, hair or mucous membrane tissue (for example oral cavity, nasopharynx, respiratory tract, stomach, genitals or body of gland, as gastrointestinal tract, mouth, lung, bronchial, nasal meatus and nasal sinuses, genitourinary tract, vagina etc.).

The infection that can treat or relevant disease comprise that fungal infection causes or relevant any fungal infection or disease, and described treatment comprises prevention (prevent or reduce the fungus contact, pollute, the susceptibility or the retransmission rate of growth, propagation or infection).The concrete non-limiting fungi that can handle according to the present invention comprises for example colter mould (Absidia), branch top spore mould (Acremonium), (Actinomadura), chain lattice spore (Altemaria), joint kettle mould (Apophysomyces), joint Pedicellus et Pericarpium Trapae spore (Arthrinium), save civilian bacterium (Arthrographis), aspergillosis (Aspergillus), short stalk mould (Aureobasidium), frog excrement mould (Basidiobolus), muscardine (Beauveria), bipolar bacterium (Bipolaris), blastogenesis yeast (Blastomyces), head division blastomyces (Blastoschizomyces), Fructus Vitis viniferae spore (Botrytis), candidiasis (Candida) (Candida albicans (C.albicans), candida krusei (C.krusei), Oidium tropicale (C.tropicalis), Candida parapsilosis (C.parapsilosis) or (C.glabrata)), hair shell (Chaetomium), gold pityrosporion ovale (Chrysosporium), prop up spore Saksenaea vasiformis (Cladophialophora), branch spore mould (Cladosporium), coccidioides immitis (Coccidioides), ear mould (Conidiobolus), Cryptococcus (Cryptococcus), little Ke Yinhan mould (Cunninghamella), curved spore (Curvularia), dermatophytes (Dermatophytes), Emmonsia, attached coccus (Epicoccum), dermatophytes (Epidermophyton), outer Saksenaea vasiformis (Exophiala), painted mould (Fonsecaea), sickle spore reaping hook mould (Fusarium), ground mould (Geotrichum), sticking broom mould (Gliocladium), sticking bundle spore (Graphium), the long spore (Helminthosporium) of wriggling, histoplasma capsulatum (Histoplasma), Weir Ni Kehede bacterium (Hortaea werneckii), Lacazia, ball cavity bacteria (Leptosphaeria), Madura bacterium (Madurella), fish-scale mould (Malassezia), Malbranchea, little spore mould (Microsporum), mucormycosis (Mucor), new Carapax Et Plastrum Testudinis shape bacterium (Neotestudina), black spore (Nigrospora), Nocard's bacillus (Nocardia), Nocardiopsis, Paecilomyces varioti (Paecilomyces), secondary coccidioides immitis (Paracoccidioides), penicillium sp (Penicillium), Phaeococcomyces, Saksenaea vasiformis (Phialophora), stem point bacterium (Phoma), hair knot joint bacterium (Piedraia), Pichia sp. (Pichia), Pneumocystis (Pneumocystis), Pseudallescheria, YRENOCHAETA (Pyrenochaeta), root Mucor (Rhizomucor), rhizopus (Rhizopus), Rhodothece glutinis (Rhodotorula), Saccharomyces (Saccharomyces), match many spores (Scedosporium), broom mould (Scopulariopsis), tumor spore (Sepedonium), shadow yeast (Sporobolomyces), sporothrix (Sporothrix), Sporotrichum (Sporotrichum), Stachybotrys atra (Stachybotrys), the handle of crawling mould (Stemphylium), strepto-belongs to (Streptomyces), mould (Syncephalastrum) altogether, torulopsis (Torulopsis), Trichoderma spp. (Trichoderma), Trichophyton (Trichophyton), trichosporon bacteria (Trichosporon), single-ended spore (Trichothecium), single every spore (Ulocladium), smut (Ustilago), wheel branch spore (Verticillium), (Wangiella) and zygomycete (Zygomycetes).

The concrete limiting examples of fungus in the animal that can handle according to the present invention comprises the dermatophytes that for example causes tinea, tinea unguium, tinea cruris and tinea pedis; Paracoccidioidomycosis; Blastomycosis; Mucormycosis; Cryptococcosis; The Blastomyces coccidioides (Coccidioides imnzatis) that causes coccidioidomycosis; The Histoplasma capsulatum (Histoplasma capsulatum) that causes histoplasmosis; Cause oidiomycotic Candida albicans (Candidaalbicans); With the Aspergillus fumigatus that causes aspergillosis (Aspergillus fumigatus).The concrete application of The compounds of this invention comprises skin (for example scalp, oxter, foot, groin), mucosa (for example oral cavity, nasopharynx, respiratory tract, stomach, genitals or body of gland, as gastrointestinal tract, mouth, bronchial, lung, nasal meatus and nasal sinuses, vagina etc.), hair, fingernail and toenail treatment.

The concrete limiting examples of the fungus in the agricultural that can handle according to the present invention or gardening zone comprises for example melasma, anthrax, ripe spot, sooty mould, the septoria musiva leaf spot, Cercospora leaf spot, rust, downy mildew, brown rot, brown spot, smut, Verrucosis, the dead arm disease, ball chamber bacterium leaf spot, the Flos Rosae Rugosae melasma, the flower gangrenosis, septoria musiva dead leaf disease, early blight and late blight, leaf mold, anthrax, ring spot, dollar spot, the leaf blight of corn, pears alternaria and leaspora spot.

The limiting examples of mycete in industrial occupancy, shopping centre and the residential area (fungus) comprises for example Stachybotrys chartarum (Stachybotus corda (Stachybotrys atra), it causes animal and human's mycotoxin to be poisoned, and relevant with " office building syndrome ".Common indoor mycete also comprises for example penicillium sp (penicillium), aspergillosis (aspergillus), Fusarium spp. (fusarium), branch's pityrosporion ovale (cladosporium) and chain lattice spore (alternaria).The dry rot fungus of timber can be caused by a plurality of kinds fungus, as Meruliporia incrassata and Serpulalacrymans.

Term " object " refers to animal, mammal normally, as primate (mankind, troglodyte, Gibbon, chimpanzee, orangutan, macaque), domestic animal (Canis familiaris L., cat, fowl), farming animals (horse, cattle, goat, sheep, pig) and laboratory animal (mice, rat, rabbit, Cavia porcellus).Object comprises animal disease model, for example the fungal disease animal model.

Be fit to comprise the object of accepting antifungal therapy at present by the object that the present invention treats, or the candidate target of antifungal therapy.Candidate target comprises the object of the risk that fungus contact, pollution or fungal infection are for example arranged.Therefore, the inventive method is applicable to the risk that treatment has the fungus contact, pollutes, grows, breeds or infect, but does not also demonstrate the object of manifest symptom.Can be defined as the risk object by the fungal infection person or by the risk person of continuing to increase of fungal infection repeatedly or often, as immunosuppressant object (HIV), accept immunosuppressant (organ or tissue's transplanting) or cell proliferation (for example anticancer) object of therapy or the candidate target of this therapy, be exposed to perhaps that maybe may there be the fungus contact in existence, pollutes, the object in growth, propagation or the environment that infects.The risk object is included in the object that uses the acrylic acid fingernail that causes tinea unguium (a kind of deck fungal infection) on one or more fingernail.Therefore, object comprises immunocompetent object, also comprises the object that immunity weakens.

The compounds of this invention comprises peptide and peptide mimics, can combine with suitable medicinal carrier, excipient and diluent.Therefore, the invention provides for example pharmaceutical composition and preparation and using method in order to treat the fungus contact, to pollute, grow, survive, breed or infect.

" pharmaceutical composition " used herein or " pharmaceutical preparation " refer to one or more The compounds of this invention as herein described or its physiologically acceptable salt or prodrug and one or more other chemical constituents, can accept or the mixture of physiologically acceptable carrier and excipient as medicine.Term " medicine can be accepted " or " can accept on the physiology " comprise the solvent compatible (aqueous solvent or nonaqueous solvent), solution, Emulsion, disperse medium, coating with administration, etc. blend absorption enhancer or delayed-action activator.Therefore, " pharmaceutical composition " or " pharmaceutical preparation " refers to suitable compositions to the object administration." the acceptable salt of medicine " refers to have the chemical compound of electric charge and counter ion.

" carrier " used herein and " excipient " comprise solvent, disperse medium, carrier, coating, diluent, etc. blend absorption delay agent, buffer agent, carrier solution, suspension, colloid, condition is activity or the function that they can not destroy active component.In addition, " excipient " be often referred to join in the pharmaceutical composition, in order to the inert substance of further help compound administration.The concrete limiting examples of excipient comprises calcium carbonate, calcium phosphate, various saccharide and starch, cellulose derivative, gelatin, vegetable oil and Polyethylene Glycol.

Can prepare Pharmaceutical composition, make it be suitable for concrete whole body, zone or partial route of administration.Therefore, Pharmaceutical composition comprises suitable carrier, diluent or the excipient of administration by all means.

Can be contained in tablet (coating or not coating), capsule (hard capsule or soft capsule), microsphere agent, Emulsion, powder, granule, crystal agent, suspending agent, syrup or the elixir for the preparation of intestinal (oral cavity) administration.Can use conventional non-toxic solid carrier to prepare solid preparation, it comprises for example pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin sodium, Talcum, cellulose, glucose, sucrose, magnesium carbonate.Auxiliary activity chemical compound (for example antiseptic, antibacterial agent, antiviral agent and antifungal) also can be incorporated in the preparation.Intestinal canal administration also can use liquid preparation.Carrier can be selected from multiple oils, comprises fossil oil, animal oil, vegetable oil or artificial oil, for example Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Oleum sesami.Suitable drug excipient comprises for example starch, cellulose, Talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, magnesium stearate, sodium stearate, monostearin, sodium chloride, defatted milk powder, glycerol, propylene glycol, water, ethanol.

Be used for intestinal, parenteral or stride mucosa and pass the pharmaceutical composition of medicine and comprise for example water preparation, salt water preparation, phosphate-buffered salt water preparation, Hank ' s solution, Ringer's mixture agent, glucose/salt water preparation and glucose solution agent.Preparation can contain in order to the auxiliary substance near physiological condition, as buffer agent, osmotic pressure regulator, wetting agent, detergent etc.Additive also can comprise other active component, as bactericide or stabilizing agent.For example, solution can contain sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, Arlacel-20 or triethanolamine oleate ester.Other parenteral formulation and method are described in Bai (1997) J.Neuroimmunol.80:65-75; Warren (1997) J.Neurol.Sci.152:31-38; And among Tonegawa (1997) J.Exp.Med.186:507-515.Parenteral formulation can be packed in ampoule, disposable syringe or the multidose vial that glass or plastics make.

Pharmaceutical composition for Intradermal or subcutaneous administration can comprise sterile diluent, as water, saline solution, fixed oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetics; Antibacterial agent is as benzylalcohol or methyl hydroxybenzoate; Antioxidant is as ascorbic acid, glutathion or sodium sulfite; Chelating agen is as ethylenediaminetetraacetic acid; Buffer agent is as acetate, citrate or phosphate and osmotic pressure regulator, as sodium chloride or glucose.

Medicinal composition for injections comprises aqueous solution agent (under water-soluble situation) or dispersant and the aseptic powder that supplies on-the-spot preparation sterile injectable solution agent or dispersant.For intravenously administrable, suitable carriers comprises normal saline, bacteriostatic water, Cremophor EL ^TM(BASF, Parsippany, NJ) or phosphate-buffered saline (PBS).Carrier can be solvent or contain for example water, ethanol, the disperse medium of polyhydric alcohol (for example glycerol, propylene glycol and liquid macrogol etc.) or their suitable mixture.Mobile can be for example by using coating such as lecithin, under the situation of dispersant, keeping required granular size and by using surfactant to keep.Antibacterial agent and antifungal comprise for example p-Hydroxybenzoate, methaform, phenol, ascorbic acid and thimerosal.Can comprise isotonic agent in the compositions, for example saccharide, polyhydric alcohol such as mannitol and sorbitol, sodium chloride.But gained solution former state packing is for use, but or lyophilizing, lyophilized formulations can make up with solution before the administration afterwards.

That the medicine acceptable carrier can comprise is stable, increase or postpone the chemical compound that absorbs or remove.This chemical compound comprises for example carbohydrate, as glucose, sucrose or glucoside; Low molecular weight protein; Reduce the clearance rate of peptide or the compositions of percent hydrolysis; Perhaps excipient or other stabilizing agents and/or buffer agent.Postpone absorbent and comprise for example monostearate aluminum and gelatin.Detergent also can be used to absorption stable or raising or reduction pharmaceutical composition, and it comprises liposome vectors.For preventing to be digested, chemical compound can be compound with compositions, makes it can resist acid hydrolysis or enzyme hydrolysis, and perhaps chemical compound can be compound in the carrier such as liposome with suitable resistance.The means that the protection chemical compound is avoided digesting are well known in the art (referring to for example Fix (1996) Pharm Res.13:1760-1764; Samanen (1996) J.Pharm.Pharmacol.48:119-135; With United States Patent (USP) 5,391,377).

For saturating mucosa or transdermal administration, in preparation, use the penetrating agent that is suitable for barrier to be infiltrated.This penetrating agent is normally well known in the art, for example for saturating mucosal drug delivery, comprises detergent, cholate and fusidic acid derivatives.Can carry out mucosal drug delivery (referring to for example Sayani (1996) " Systemic delivery of peptides andproteins across absorptive mucosae " Crit.Rev.Ther.Drug Carrier Syst.13:85-184) by nasal mist or suppository.For transdermal administration, chemical compound can be mixed with ointment well known in the art, ointment, gel, foam, spray or cream.Can use any cream base of dermatological purposes.For suppository, glycerol or paraffin thickening agent such as the hydroxypropyl emthylcellulose with routine can be used, to regulate viscosity.Also can use patch to realize transdermal delivery system.

Pass medicine for suction, pharmaceutical preparation can aerosol or the form administration of spray.For aerosol drug delivery, preparation can particulate form be supplied with surfactant and propellant.In another embodiment, preparation is being vaporized in the device of respiratory tissues in order to delivery formulation.Other delivery systems well known in the art comprise that dry powder aerosol, liquid delivery system, inhaler, air-blast atomizer and Propellant System are (referring to for example Patton (1998) Biotechniques 16:141-143; Dura Pharmaceuticals, San Diego, CA; Aradigm, Hayward, CA; Aerogen, Santa Clara, CA; With Inhale TherapeuticSystems, San Carlos, CA).

Can use biodegradable, biocompatible polymer, as vinyl-vinyl acetate copolymer, polyanhydride, polyglycolic acid, collagen, poe and polylactic acid.The method for preparing this prescription is well known in the art.This material also can be from Alza Corporation and NovaPharmaceuticals, the commercially available acquisition of Inc.Liposome suspension (comprising the liposome that uses antibody or virus envelope proteins guiding cell or tissue) is the useful as drug acceptable carrier also.Described liposome suspension can be according to method preparation well known in the art, and this method for example is described in United States Patent (USP) 4,235,871; 4,501,728,4,522,811,4,837,028,6,110,490,6,096,716,5,283,185,5,279,833; Akimaru (1995) Cytokines Mol.Ther.1:197-210; Alving (1995) Immunol.Rev.145:5-31; And Szoka (1980) Ann.Rev.Biophys.Bioeng.9:467).Can continue to send the biodegradable microsphere of micromolecule (comprising peptide) or capsule or other biological degradable polymer structure is (referring to for example Putney (1998) Nat.Biotechnol.16:153-157) well known in the art.The compounds of this invention can be incorporated in the micelle (referring to for example Suntres (1994) J.Pharm.Pharmacol.46:23-28; Woodle (1992) Pharm.Res.9:260-265).Peptide is adsorbable to the surface of lipid monolayer or lipid bilayer.For example, peptide is adsorbable to the liposome that contains hydrazides-PEG-(distearyl acyl group phosphatidyl) ethanolamine (referring to for example Zalipsky (1995) Bioconjug.Chem.6:705-708).In addition, can use any type of adipose membrane, as the cell membrane of plane adipose membrane or intact cell (as erythrocyte).Liposomal formulation and contain the fat preparation and can send by any way, for example comprise intravenous administration, transdermal administration (referring to for example Vutla (1996) J.Pharm.Sci.85:5-8), saturating mucosal drug delivery or mouthful in administration.

The acceptable preparation of medicine can mix the active component (for example peptide and peptide mimics) of about 0.11%-99.9%.Pharmaceutical composition can be sterilized by well-known conventional sterilization technology, but or filtration sterilization.

Other pharmaceutical preparation and delivery system are well known in the art, and they can be applicable in the method and composition of the present invention (referring to for example Remington ' s Pharmaceutical Scieces(1990) the 18th editions, Mack Publishing Co., Easton, PA; The Merck Index(1996) the 12nd editions, Merck Publishing Group, Whitehouse, NJ; Pharmaceutical Principles of Solid Dosage Forms, Technonic PublishingCo., Inc., Lancaster, Pa., (1993); With Poznansky etc., Drug Delivery Systems, R.L.Juliano (editor), Oxford, N.Y. (1980), 253-315 page or leaf).

Pharmaceutical preparation can be packaged into single dose form, to make things convenient for the concordance of administration and assurance dosage." single dose form " used herein refers to physically discrete unit dose, for delivering medicine to object to be treated; Constituent parts contains the predetermined quantitative compound that can produce required effect and the combination of pharmaceutical carrier or excipient." many units " dosage form refers to multiple physically discrete unit, and the constituent parts of packing carries out the unit administration by the therapeutic scheme that produces required effect.

The compounds of this invention also can be united use with any treatment with antifungal activity or antifungal function.Therefore, can by with The compounds of this invention with can directly or indirectly suppress the therapeutic combination that fungus contacts, pollutes, grows, survives, breeds or infects, improve, strengthen, collaborative or prolong antifungal activity.Also can by with The compounds of this invention with can suppress or suppress fungus and contact, pollute, grow, survive, breed or infect, perhaps can reduce treatment (no matter whether this treatment can damage nucleic acid) combination, improve, strengthen, work in coordination with or prolong antifungal activity the susceptibility of fungus contact, pollution, growth, propagation or infection.Therefore, the present invention further provides compositions and the using method that comprises The compounds of this invention (for example peptide or peptide mimics) and antifungal therapy or antifungal (for example nucleic acid damaging agents).

Term used herein " antifungal therapy " refers to directly or indirectly to suppress or to reduce conk, pollution or infection with " antifungal " or with conk, pollution or infect relevant symptom or disease, perhaps can reduce or reduce any therapeutic scheme or the medicament of the retransmission rate or the susceptibility of conk, pollution or infection, and no matter its model of action how, whether for example described treatment or medicament can damage nucleic acid.The instantiation of antifungal comprises the medicine that suppresses cell proliferation.Concrete example comprises especially cyclophosphamide, azathioprine, cyclosporin A, prednisolone, melphalan, chlorambucil, chlormethine, hundred disappear peace, methotrexate, Ismipur, thioguanine, cytosine arabinoside, taxol, vinblastine, vincristine, doxorubicin, radiating streptozotocin D, plicamycin, carmustine, lomustine, semustine, chain azoles toxin, hydroxyurea, cisplatin, mitotane, procarbazine, dacarbazine and mitobronitol.Cause the antiproliferative of nucleic acid replication mistake or inhibition nucleic acid replication to comprise nucleoside and nucleotide analog, as AZT and 5-AZC.

The suitable antifungal that uses in animal (for example human) or agricultural comprises allylamine (amrolfine, butenafine, naftifine, terbinafine), pyrroles's (ketoconazole, fluconazol, elubiol, econazole, econaxole, itraconazole, isoconazole, imidazoles, miconazole, sulconazole, clotrimazole, enilconazole, oxiconazole, tioconazole, terconazole (triaconazole), butoconazole, thiabendazole, voriconazole, Saperconazole, Sertaconazole, fenticonazole, posaconazole, bifonazole, flutrimazole), polyenoid (nystatin, natamycin, amphotericin B), pyrimidine (flucytosine), tetraene (natamycin), thiocarbamate (tolnaftate), sulfonamide (mafenide, dapsone), glucosan synthetic inhibitor (Caspofungin), benzoic acid compounds, their complex and derivant (actofunicone) and other system are used or mucosa medicine (griseofulvin, potassium iodide, Gentian Violet) and topical drug's (ciclopirox, ciclopirox olamine, haloprogin, undecylenate salt, silver sulfadiazine, undecylenic acid, the undecylenic acid alkanolamide, carbolfuchsin).Other suitable antifungal that use in animal for example are described in Physicians Desk Reference, the 57th edition, in November, 2002, Medical EconomicsCompany.

The suitable antifungal that uses in agricultural or gardening comprises Mancozeb, maneb, Banner Maxx, Compass Cleary ' s, triforine, and that yellow grand, the Mancozeb of Immunox, zineb, sulphur ammonia, nitrile bacterium azoles, holder are pounced on is clean, captan, thiram, carboxin, metalaxyl, PCNB, CGA-173506, thiabendazole, cuprio antifungal (for example COPPER OXYCHLORIDE 37,5), sulfur-containing compound, citrus oils and bacillus subtilis.Other suitable antifungal that use in agricultural for example are described in Fungicides in Plant Disease Control, the 3rd edition, Nen and Thapliyal, 1993, Science Publishers Inc..

The suitable antifungal that uses in industrial occupancy, residential area, community and shopping centre comprises for example detergent, bleach, OMACIDE ^IPBC (3-iodine propinyl butyl carbamate), Fungitrol ^, Nuocept ^, microban, citrus oils and chromated copper arenate (timber preservative).

Term used herein " nucleic acid damaging treatment " and " nucleic acid damaging agents " refer to directly or indirectly to damage any therapeutic scheme of nucleic acid (for example DNA, cDNA, genomic DNA, mRNA, tRNA or rRNA).The instantiation of this medicament comprises alkylating agent, nitroso ureas, antimetabolite, plant alkaloid, plant extract and radiosiotope.The instantiation of this medicament also comprises the nucleic acid damaging medicine, 5-fluorouracil (5-FU) for example, capecitabine, S-1 (ftorafur, 5-chloro-2,4-dihydroxy-pyridine and 1,4,5,6-tetrahydrochysene-4,6-dioxy-1,3,5-triazine-2-carboxylic acid), 5-ethinyluracil, cytosine arabinoside (ara-C), 5-azacytidine (5-AC), 2 ', 2 '-two fluoro-2 '-deoxycytidine (dFdC), purine antimetabolite (purinethol, azathioprine, thioguanine), gemcitabine hydrochloride (strong selecting), pentostatin, allopurinol, 2-fluoro-arabinosyl adenine (2F-ara-A), hydroxyurea, sulfur mustard gas (yperite), chlormethine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, plug is for group, AZQ, ametycin, two anhydrous galactitols, mitolactol, alkylsulfonate (hundred disappear amine), nitroso ureas (BCNU, CCNU, 4-Methyl CCNU or ACNU), procarbazine, dacarbazine (decarbazine), the rebecca mycin, anthracycline such as doxorubicin (amycin; ADR), daunorubicin (Cerubicine), idarubicin (Idamycin) and epirubicin (Ellence), similar thing of anthracycline such as mitoxantrone, radiating streptozotocin D, non-embedding topoisomerase enzyme inhibitor such as epipodophyllotoxin (etoposide=VP16, teniposide=VM-26), podophyllotoxin, bleomycin (Bleo), peplomycin, form the chemical compound of adduct with nucleic acid, comprise platinum derivatives (cisplatin (CDDP) for example, the trans analog of cisplatin, carboplatin, iproplatin, four platinum and oxaliplatin), camptothecine, hycamtin, irinotecan (CPT-11) and SN-38.The instantiation of nucleic acid damaging treatment comprise radiation (for example ultraviolet (UV) radiation, infrared ray (IR) radiation or α-, β-or γ-radiation) and environmental impact (for example high temperature).

The inventive method and compositions (comprising peptide and peptide mimics) can provide the medicament of benefit or treatment to unite use with other.For example, fungus contact, pollution, growth, propagation or infection often are accompanied by other pathogen, as antibacterial, virus and parasite.Specifically, the object of fungus opportunistic infection risk is arranged, for example also there is the risk of virus, antibacterial, parasitic infection and other infection in immunocompromised patient (for example because organ or tissue transplants or HIV infects).Therefore, antimicrobial or treatment (antiviral agent or antibacterial agent or antiparasitic) can be united use with peptide of the present invention or peptide mimics.Therefore, the invention provides the method and composition that comprises with the combination of antibacterial, virus and parasite treatment and medicament.

In addition, fungus contact, pollution, growth, propagation or infection can cause inflammation.Therefore, anti-inflammatory agent or anti-inflammatory treatment can be united use with peptide of the present invention or peptide mimics compositions or method.Fungus contact, pollution, growth, propagation or infection also can cause pain or swelling.Therefore, analgesic or analgesic or analgesia or pain management can be united use with peptide of the present invention or peptide mimics.

Anti-inflammatory agent or anti-inflammatory treatment comprise for example based on steroid and nonsteroidal medicine and therapy.Steroidal antiinflammatory drug comprises glucocorticoid.The limiting examples of steroid comprises fluocinolone acetonide, triamcinolone, triamcinolone acetonide, betamethasone, betamethasone dipropionate, diflucortolone, fluticasone, cortisone, hydrocortisone, mometasone, methylprednisolone, beclometasone, clobetasol, prednisone, prednisolone, methylprednisolone, betamethasone, budesonide, dexamethasone etc.The limiting examples of nonsteroid anti-inflammatory drugs comprises celecoxib, nimesulide, rofecoxib, meclofenamic acid, meclofenamic acid sodium, flunixin, fluprofen, flurbiprofen, sulindac, meloxicam, piroxicam, etodolac, fenoprofen, fragrant ibuprofen (fenbuprofen), ketoprofen, suprofen, diclofenac, bromfenac sodium, Phenylbutazone, Thalidomide and indomethacin.

Analgesic and analgesic and analgesia or pain management (some of them have anti-inflammatory activity) comprise that aspirin, acetaminophen, ibuprofen, naproxen, procaine, lignocaine, tetracaine, cincaine, benzocaine, hydrochloric acid are to butyl amino benzoic Acid 2-(diethylamino) ethyl ester, mepivacaine, piperocaine and dyclonine.Other analgesic comprise opiates, for example morphine, codeine, hydrocodone and oxycodone.

Antiviral agent or antiviral therapy can suppress, reduce or eliminate virus replication, propagation or virus replication or breed symptom or disease relevant or that cause.Therefore, antiviral agent and antiviral therapy comprise any medicament or the treatment that can suppress, reduce, prevent or alleviate viral infection or generation in any step of viral life cycle or stage, any step of described viral life cycle or stage for example virus by cell surface receptor or without cell surface receptor and cell fusion; Viral nucleic acid enters cell; The reverse transcription of viral nucleic acid; Retroviral nucleic acid is incorporated into the genome of cell; Provirus transcribed nucleic acid or duplicate; The translation or the formation of ripe virus protein; Formation/the assembling of infectious virus particle; Ripe virion is from cell blastogenesis or release.

The concrete limiting examples of antiviral agent comprises viral fusion inhibitor, for example T20 and T20 analog (Trimeris company); Non-nucleoside reverse transcriptase inhibitor (for example nevirapine, delavirdine, efavirenz); Protease inhibitor (for example Saquinavir, ritonavir, indinavir, viracept see nelfinaivr, ammonia Pune Wei); The thymidine kinase inhibitor; Sugar or glycoprotein synthetic inhibitor; The structural protein synthetic inhibitor; Nucleoside analog (for example zidovudine (AZT), stavudine (d4T), larnivudine (3TC), didanosine (DDI), zalcitabine (ddC), Abacavir, acyclovir, penciclovir, valaciclovir and ganciclovir); And virus maturation inhibitor (for example " zinc refers to infusion appliance ", it suppresses the assembling of viral α nucleocapsid protein, thereby prevents to form infectious virus particle).

Be fit to determine by the existence that detects fungus in the described concrete zone by industrial occupancy, residential area, community, shopping centre, farming region, gardening zone and environment that the present invention handles.For example, for determining whether fungus is present in the building, can sample at indoor and outdoors.If it is outdoor that indoor fungus amount surpasses, there is the pollution of fungus so probably.For example, can check the air in building or other buildings, see whether there is mycete.Can roughly estimate quantity and the variety classes of mycete granule (spore and conidium) by the mycete granule that drops on filter or the slide is carried out microscopy.In addition, airborne any fungus also can drop on the growth medium.Carry out grown cultures at laboratory and can accurately identify the airborne fungus alive of sampling place.Also can find the existence of fungus by visual examination.For example, can observe building or other body structure surfaces or inner fungus growth.Can check the content of the sack of vacuum cleaner, perhaps can be from body surface wiping sample, perhaps can downcut and identify the material piece of fungus of as if growing.

The compounds of this invention can be before fungal infection, pollution or growth, simultaneously, afterwards, before adopting other treatment scheme or medicament, simultaneously, give afterwards.Therefore, the invention provides the method for the retransmission rate of method of prophylactic treatment and minimizing or the contact of inhibition fungus, pollution, growth, propagation or infection.

Therefore, the present invention also provide in order to suppress, reduce with reduce external, earlier external back body in the combined method and the treatment that contact, pollute, grow, survive, breed and infect with fungus in the body.Can comprise any antifungal disclosed herein or well known in the art, nucleic acid damaging or antineoplaston or medicament with the treatment that The compounds of this invention is united use.For example, the chemotherapy treatment can comprise the radiotherapy that is undertaken by external source radiation or radiosiotope internalization, optional bound drug treatment.Therefore, treatment can comprise and give chemical substance such as radiosiotope, perhaps medicine such as chemotherapeutics.

The dosage of treatment is " effective dose " or " q.s " normally, promptly is enough to produce the amount that needs effect.Therefore, effective dose comprises following or some: with respect to suitable contrast, suppress or reduce the fungus contact, pollute, growth, propagation or the susceptibility or the retransmission rate that infect; Reduce, reduce or inhibition fungal contamination, growth, existence, propagation or infection (for example reducing or eliminating the fungal cell); And reduce or reduce fungus contact, pollution, growth, existence, propagation or infect one or more symptoms of being correlated with or causing.Therefore, described amount can be enough to reduce to infect or make infect stable (for example suppress or prevent fungal contamination, growth, propagation or infection, perhaps fungus contact, pollute, growth, propagation or infect the development or the deterioration of relevant or one or more symptoms of causing).Therefore, think that effective amount can prevent or suppresses to infect or relevant disease or advancing of disease.

Effective dose can be objectively or subjectively reduce or reduce the fungus contact, pollute, growth, existence, propagation or infect one or more symptoms relevant or that cause, the perhaps seriousness of Xiang Guan disease or disease, occurrence frequency or persistent period.For example, can reduce itch, the The compounds of this invention amount of seriousness, occurrence frequency or the persistent period of inflammation, pain, ejection or other any symptoms or associated conditions is satisfactory clinical endpoint.Effective dose also can be realized the improvement of histology aspect.

Effective dose also comprises amount (for example dosage) or the therapeutic frequency that reduces another kind of antifungal therapy, and this minimizing can be thought satisfactory clinical endpoint.For example, the object of accepting The compounds of this invention treatment can need nucleic acid damaging treatment still less can treat fungal infection.Effective dose can comprise that the dose frequency or the dosage of antifungal therapy compared when treating without The compounds of this invention, reduces the dose frequency of uniting when using The compounds of this invention to treat or the amount of dosage.

The amount that " treatment effective dose " refers to reduce or to improve fungus contact, pollution, growth, existence, propagation or infect one or more symptoms of being correlated with or causing, described improvement are " improvement " of object disease or " the treatment benefit " of giving object.

" prevention effective dose " refers to reduce or reduce the amount to the susceptibility of fungal contamination, growth, propagation or infection; Perhaps keep by inhibition fungal cell growth that gives the realization of antifungal therapy or antifungal or the amount of breeding; Perhaps keep the propagation by giving the inhibition fungal infection that antifungal therapy or antifungal realize or the amount of deterioration; Perhaps keep to reduce fungal contamination, growth, propagation or infection causes or the amount of relevant one or more symptoms.The prevention effective dose also refers to suppress or to prevent fungus contact, the amount of polluting, growing, breed or infect susceptible object (for example lived organism).When word " improvement " had fungus contact, pollution, growth, propagation or infection or the object of this risk is arranged when finger, synonym used.

The representative consumption of CBP501 is about 1-20uM (external), or about 2-40ug/ml.The representative consumption of the whole body of CBP501 is about 1-10mg/kg, or about 3-30mg/mm (vein); Or about 5-50mg/kg, or about 15-150mg/mm (intraperitoneal).Amount in mm is all basic identical in most of animals, and therefore, for example in the mankind, the amount during transfusion is about 3-30mg/mm.Use for the part, every square centimeter of about 20 micrograms of skin should be enough.

Causing the object disease to take a turn for the better or persistent period of the inventive method of therapeutic effect occurs may be shorter relatively, for example takes a turn for the better sustainable a few minutes of time, several hours, several days or a few week, and perhaps the inventive method can continue the longer time, for example some months or several years.Therefore, effective dose is unnecessary removes or eliminates the fungus contact fully, pollute, growth, existence, propagation or infect, perhaps fungus contact, pollute, growth, existence, propagation or infect any or all symptom relevant or that cause.Therefore, when employing is suitable for determining fungus contact, pollution, growth, existence, propagation or the state or the degree that infect, perhaps be fit to determine fungus contact, pollution, growth, existence, propagation or the susceptibility that infects or any aforesaid standards or other standards well known in the art of retransmission rate, in short or long period of time, determine, the disease of finding object has subjectivity or when objectively taking a turn for the better, promptly reaches the satisfactory clinical endpoint of effective dose.

Can determine the effective dose of The compounds of this invention treatment target based on comparing in the external and known amount that under given concentration or dosage, in animal, has active antifungal.For example, can use the susceptibility test to determine following chemical compound Cmin: the concentration that suppresses or reduce conk or propagation; Suppress or the concentration (minimal inhibitory concentration, MFC, μ g/ml) of minimizing fungus amount or the concentration (minimal bactericidal concentration, MFC, μ g/ml) of kill fungi.In addition, can use zooscopy, comprise that people's clinical trial determines effective dose.

Those of ordinary skills can know, various factors can influence treatment concrete object required dosage and opportunity, comprise for example general health situation, age or the sex of object, the order of severity of disease or disease or stage, the treatment of in the past accepting, to the susceptibility of adverse side effect, need the clinical effectiveness that obtains and whether have other diseases or disease.This factor may be provided required dosage and the opportunity of amount that is enough to produce therapeutic effect that provide.

In being used for the treatment of the inventive method of object, can give The compounds of this invention on (organ or tissue of for example leading) or the part on whole body, the zone according to any scheme or the approach that needing to realize effect.But The compounds of this invention every day with single dose or multiple dose administration (for example adopting low dosage), (for example every other day, wait weekly, adopt high dose) or administration continuously discontinuously, specifically can determine by specialist.Chemical compound and pharmaceutical composition, comprise one or more compositionss or their combination separately, can by suck (for example in the trachea), mouthful in, in the intravenous, intra-arterial, blood vessel, in the sheath, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal (for example local), saturating mucosa (for example oral cavity, vagina, uterus, rectum or nose) administration, can be multiple dosing, (for example transfusion continuously, long-time gradient transfusion or adopt capsule) or the heavy dose of administration of single continue medication.

The chemical compound of topical gives with the unit dose of 1mg/mL-1gm/mL usually, and perhaps the dosage with 1mg/mL-100mg/mL gives.The chemical compound of intravenous (IV) administration normally in several hrs (normally 1,3 or 6 hour) about 0.01mg/hr to about 1.0mg/hr, but this intermittent cyclic is carried out all or several weeks repeatedly.The daily dose that gives one or more times usually every day 0.1mg/kg-100mg/kg, every day 0.1mg/kg-20mg/kg or every day 1mg/kg-20mg/kg scope in.Can use higher relatively dosage (for example up to about 10mg/ml), particularly when local or regional administration, and medicine does not enter when (for example not entering body cavity or entering organ such as the inner chamber of vagina) in the blood flow.Those of ordinary skills can easily determine to reach the effective dose and the dosage regimen of therapeutic effect.

Chemical compound can be used slow-released system, passs medicine as the semipermeability substrate of solid hydrophobic polymer.Slow-released system and method comprise that the little assembling device that is used for continuing to pass medicine in inside is well known in the art.

The present invention also provides the medicine box that comprises The compounds of this invention and pharmaceutical preparation thereof, and medicine box is optional to be packed with suitable packaging material.Medicine box generally includes label or package insert, and it comprises that component description and this component are in the body of external, earlier external back or in the body, in environment, in agricultural or gardening zone or the operation instruction in shopping centre, industrial occupancy, residential area or community.The optional tabulation that comprises the concrete fungi kind that is fit to treatment of label.Medicine box can comprise multiple such component, for example the combination of two or more The compounds of this invention or a kind of The compounds of this invention and a kind of antifungal.

Term " packaging material " refers in order to store the physique of kit components.Packaging material can make component keep aseptic condition, and it can be made (for example paper, corrugated fiber, glass, plastics, metal, metal forming, ampoule etc.) by the material that is generally used for this type of purpose.Label or package insert can comprise suitable written explanation.Therefore, medicine box of the present invention can comprise label or the description of using kit components with any method of the present invention in addition.Description can comprise the explanation of implementing any bright method described herein.Therefore, for example medicine box can comprise the The compounds of this invention that is contained in container or the delivery apparatus, and the description that gives chemical compound by Therapeutic Method of the present invention.Description can comprise the explanation of satisfactory clinical endpoint or any ill symptoms that may occur in addition, perhaps the relevant additional information of using in human subjects of administrative organization such as U.S. food and Drug Administration's requirement.

Description can be on " printed article ", for example in medicine box or invest on the paper or hardboard of medicine box, perhaps on the label that invests medicine box or packaging material, perhaps is attached on the bottle or tubule that component is housed.In addition, description also can be stored in the computer-readable medium, as the mixture such as the magnetic/optical storage medium of disk (floppy disk or hard disk), CD such as CD-or DVD-ROM/RAM, tape, electronic storage medium such as RAM and ROM, IC contact and above medium.

In addition, medicine box of the present invention can comprise buffer agent, antiseptic or stabilizing agent in pharmaceutical preparation.Each component of medicine box can be contained in the independent container, and all each containers can be contained in the individual packaging.Medicine box of the present invention can be designed to be suitable for cold preservation.

The present invention also provides the article that hold The compounds of this invention and pharmaceutical preparation thereof in addition.Term defined herein " object " should comprise article.

Article comprise machinery, apparatus, instrument, device, the packaging material that can contact fungus, perhaps any organic or inorganic material (for example construction material or medical material).

All terms of this paper " medical material " refer to use in health care, may be exposed to any object of patient or object in inspection, diagnosis or therapeutic process.The concrete limiting examples of medical material comprises stitching thread, wound dressing (sealing or semiclosed fabric, for example gauze pad or binder), local with gauze, bonding film, hard dressing, adhesive tape and fastener.The other limiting examples of curing all materials comprises examination glove, operation dress and mask, syringe and entry needle.

In addition, the present invention also provide peptide of the present invention and peptide mimics (for example with sequence that this paper proposes have 90% or higher conforming sequence) or its prodrug be enough to suppress, reduce or prevent application in the medicine that fungus contacts, pollutes, grows, breeds or infect in preparation.Described medicine is optional to comprise other medicaments, as antimicrobial, anti-inflammatory drug or analgesic, and perhaps acceptable or physiology acceptable carrier or excipient of medicine.

The invention provides the method for identifying and screening chemical compound with antifungal activity or function.Evaluation and screening technique can (in animal) carry out in solution or in solid phase, external (cell or tissue cultivation), earlier external back body or in the body.

In one embodiment, described method comprises that the chemical compound that enables to eliminate or suppress the G2 outpost of the tax office contacts with fungus; Fungus is cultivated with chemical compound; Determine existence, growth or the propagation of fungus then.Fungus survives when chemical compound exists, grows or breeds to reduce proves that this chemical compound has antifungal activity.In another embodiment, described method comprises that the chemical compound that enables to eliminate or suppress the G2 outpost of the tax office contacts with fungus; Fungus is cultivated with chemical compound; Determine existence, growth or the propagation of fungus then.In going back an embodiment, described method comprises makes peptide or peptide mimics contact with fungus; Fungus is cultivated with peptide or peptide mimics; Determine existence, growth or the propagation of fungus then.Fungus existence when peptide or peptide mimics exist, growth or propagation reduces this peptide of proof or peptide mimics has antifungal activity.In another embodiment, described method comprises makes peptide or peptide mimics contact with fungus; Fungus is cultivated with peptide or peptide mimics; Determine existence, growth or the propagation of fungus then.

This paper has used following abbreviation:

Cha: Cyclohexylalanine

Phe-2,3,4,5,6-F: fluorine 2,3,4,5,6 on the phenyl residues of phenylalanine

F: fluorine

Bpa: benzyl acyl group-phenylalanine

Nal (2): 2-naphthyl-alanyl

Ala (3-Bzt): (3-benzothienyl) alanine

Nal (1): 1-naphthyl-alanyl

Dph: xenyl-alanine

Ala (tBu): the tert-butyl group-alanyl

Cys (tBu): the tert-butyl group-cysteine

Phe-3,4,5-F: fluorine 3,4,5 on the phenyl of phenylalanine

Phe-4CF3:CF3 4 on the phenyl residues of phenylalanine

Phe-3Br, 4Cl, 5Br: bromine is at 3 of the phenylalanine phenyl, and chlorine is at 4, and bromine is at 5

Phe-4Cl: chlorine 4 on the phenyl of phenylalanine

P1, P2, P3, P4, P5, P6 etc. and (P1, P2, P3, P4, P5, P6 etc.); P7, P8, P9, P10, P11, P12 etc. and (P7, P8, P9, P10, P11, P12 etc.); X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁: be respectively P1, P2, P3, P4, P5, P6 etc.; P7, P8, P9, P10, P11, P12 and X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁Contiguous nucleotide sequence

X: any aminoacid.

Unless define in addition, all technology used herein are the same with the implication of those skilled in the art's common sense with scientific terminology.Although can be applied in enforcement of the present invention or the test being similar to or equaling method described herein and material, this paper has described suitable method and material.

All publications that this paper quotes, patent and other lists of references integral body by reference are attached to herein.If any conflict, be as the criterion with this description (comprising definition wherein).

Except that context clearly indicated, this paper used singulative " " " a kind of " to comprise plural implication.Therefore, if suitable, for example " chemical compound " comprises multiple chemical compound, and " peptide " or " aminoacid " comprises one or more peptides and aminoacid.

The invention describes a plurality of embodiments.However, it will also be appreciated that and to make various modifications and without departing from the spirit and scope of the present invention.Therefore, following examples are intended to the explanation rather than the described scope of the invention of restriction claims.

Embodiment

Embodiment 1

Present embodiment is described material and several method.

Chemicals and reagent(St.Louis MO), is dissolved in DMSO with it, to 10mg/ml to amphotericin B available from Sigma-Aldrich company.Boromycin and L, L-D42067 α is so kind as to give by professor H.Tomoda of university in the north.

Cell cultureSaccharomyces cerevisiae (Saccaromices Cerevisie) AH109 available from CLONTECH (Palo Alto, CA).The YAPD flat board is used available from the YPD Agar of CLONTECH with available from the preparation of the adenine of Sigma-Aldrich company.Cell is cultivated under 30 degree.

Embodiment 2

Present embodiment is described the structure of all cpds of the present invention.Table 1 has been enumerated various peptide/peptide mimicses, and ((d-Bpa) be (d-Trp) (d-Ser) (d-Phe2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)) (d-Ser) to comprise CBP501.

The representative peptide of table 1/peptide mimics sequence and corresponding numbers

(l-Tyr)(l-Gly)(l-Arg)(l-Lys)(l-Lys)(l-Arg)(l-Arg)(l-Gln)(l-Arg)(l-Arg)(l-Arg)(l-Cha)(l-Phe-2，3，4，5，6，-F)(l-Arg)(l-Ser)(l-Pro)(l-Ser)(l- Tyr)(l-Tyr)(SEQ ID NO：116)	CBP413
	CBP413	(l-TYr)(l-Gly)(l-Arg)(l-Lys)(l-Lys)(l-Arg)(l-Arg)(l-Gln)(l-Arg)(l-Arg)(l-Arg)(l-Cha)(l-Phe-2，3，4，5，6-F)(l-Arg)(l-Ser)(l-Pro)(l-Ser)(l-Tyr) (SEQ ID NO：117)	CBP420
(l-Arg)(l-Arg)(l-Arg)(l-Cha)(l-Phe-2，3，4，5，6-F)(l-Arg)(l-Ser)(l-Pro)(l-Ser)(l-Tyr)(l-Tyr)(SEQ ID NO：118)	CBP430		CBP420
	CBP430	(l-Arg)(l-Arg)(l-Gln)(l-Arg)(l-Arg)(l-Arg)(l-Cha)(l-Phe-2，3，4，5，6-F)(l-Arg)(l-Ser)(l-Pro)(l-Ser)(l-Tyr)(l-Tyr)(SEQ ID NO：119)	CBP431
(l-Arg)(l-Arg)(l-Gln)(l-Arg)(l-Arg)(l-Arg)(l-Cha)(l-Phe-2，3，4，5，6-F)(d-Ser)(d-Trp)(l-Pro)(l-Ser)(l-Tyr)	CBP432		CBP431
	CBP432	(l-Tyr) (l-Gly) (l-Arg) (l-Lys) (l-Lys) (l-Arg) (l-Arg) (l-Gln) (l-Arg) (l-Arg) (l-Arg) (l-Cha) (l-Phe-2,3,4,5,6-F) (the amino hendecanoic acid of l-) (l-Tyr) (l-Tyr) (SEQ ID NO:120)	CBP440
(d-Tyr)(d-Tyr)(d-Ser)(l-Gly)(d-Ser)(d-Arg)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)(d-Lys)(d-Lys)(d- Arg)(l-Gly)(d-Tyr)	CBP450		CBP440
	CBP450	(d-Tyr)(d-Ser)(d-Pro)(l-Trp)(l-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP451
(d-Tyr)(d-Ser)(l-Pro)(l-Trp)(l-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP452		CBP451
	CBP452	(d-Tyr)(d-Ser)(d-Pro)(l-Trp)(l-Ser)(d-Phe-2，3，4，5，6-F)(d-Pro)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP454
(d-Tyr)(d-Ser)(l-Pro)(l-Trp)(l-Ser)(d-Phe-2，3，4、5，6-F)(l-Pro)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP455		CBP454
	CBP455	(l-Tyr) (l-Tyr) (l-amino hendecanoic acid) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Lys) (d-Lys) (d-Arg) (l-Gly) (d-Tyr)	CBP460
(l-Tyr) (the amino hendecanoic acid of l-) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arp) (d-Gln) (d-Arg) (d-Arg) (d-Lys) (d-Lys) (d-Arg) (l-Gly) (d-Tyr)	CBP461		CBP460
	CBP461	(l-Tyr) (the amino hendecanoic acid of l-) (d-Phe-2,3,4,5,6-F) (d-Cha)	CBP462
(the amino hendecanoic acid of l-) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg) (d-Lys) (d-Lys) (d-Arg) (l-Gly) (d-Tyr)	CBP463		CBP462
	CBP463	(the amino hendecanoic acid of l-) (d-Phe-2,3,4,5, e-F) (d-Cha)	CBP464
(l-amino hendecanoic acid) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)	CBP465		CBP464
	CBP465	(l-8-aminocaprylic acid) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)	CBP466
(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP470		CBP466
(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP470	(d-Cha)(d-Phe-2，3，4，5，6-F)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP471
(d-Tyr)(d-Ser)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP481		CBP471
	CBP481	(d-Tyr)(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP500
(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP501		CBP500
	CBP501	(d-Bpa) (l-8-aminocaprylic acid) (d-Cha) (d-Phe-2,3,4,5,6-F) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)	CBP502
(d-Bpa) (l-8-aminocaprylic acid) (d-Phe-2,3,4,5,6-F) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)	CBP503		CBP502
	CBP503	(d-Asp)(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP504
(d-Bpa)(d-Asp)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP505		CBP504
	CBP505	(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Asp)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP506
(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)(d-Cha)(d-Phe-2，3，4，5，6-F)(d-Ser)(d-Trp)(d-Ser)(d-Bpa)	CBP510		CBP506
	CBP510	(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP511
(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Cha)(d-Phe-2，3，4，5，6-F)(d-Ser)(d-Trp)(d-Ser)(d-Bpa)	CBP512		CBP511
	CBP512	(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Bpa)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP601
(d-Bpa) (l-8-aminocaprylic acid) (d-Bpa) (d-Cha) (d-Arg) (d-Arg) (d-Arg) (d-Gln) (d-Arg) (d-Arg)	CBP602		CBP601
	CBP602	(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe4No2)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP603
(d-Bpa)(d-Pro)(d-Trp)(d-Pro)(d-Phe4NO2)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP604		CBP603
	CBP604	(d-Bpa)(d-Pro)(d-Trp)(d-Pro)(d-Phe4NO2)(d-Nal2)(d-Arg)(d-Ag)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP605
(d-Phe4NO2)(d-Pro)(d-Trp)(d-Pro)(d-Phe4NO2)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Gln)(d-Arg)(d-Arg)	CBP606		CBP605
	CBP606	(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg(d-Arg)(d-Arg)	CBP607
(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Arg)	CBP608		CBP607
	CBP608	(d-Bpa)(d-Ser)(d-Trp)(d-Ser)(d-Phe-2，3，4，5，6-F)(d-Cha)(d-Lys)(d-Lys)(d-Lys)(d-Lys)(d-Lys)(d-Lys)	CBP609
(d-Arg)(d-Arg)(d-Bpa)(d-Arg)(d-Arg)(d-Arg)(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP700		CBP609
	CBP700	(d-Arg)(d-Arg)(d-Arg)(d-Bpa)(d-Arg)(d-Trp)(d-Arg)(d-Phe-2，3，4，5，6-F)(d·Cha)	CBP701
(d-Arg)(d-Arg)(d-Arg)(d-Arg)(d-Bpa)(d-Arg)(d-Trp)(d-Arg)(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP702		CBP701
	CBP702	(d-Arg)(d-Arg)(d-Arg)(d-Bpa)(d-Arg)(d-Arg)(d-Arg)(d-Phe-2，3，4，5，6-F)(d-Cha)	CBP703
(d-Bpa)(d-Cys)(d-Trp)(d-Arg)(d-Phe-2，3，4，5，6F)(d-Cha)(d-Cys)	CBP524		CBP703
	CBP524	(d-Tyr)(d-Cys)(d-Pro)(d-Trp)(d-Arg)(d-Phe-2，3，4，5，6F)(d-Cha)(d-Cys)	CBP721

Embodiment 3

The phosphorylation of present embodiment summary CBP501 suppresses active.As shown in Figure 1, compare with PKC with the kinases PKA of other serine-threonine kinases such as cyclin dependent, the CBP501 strong inhibition relates to the activity of kinases such as ATM, ATR, CHK1, CHK2, PLK1 and the Weel at the cell cycle G2 outpost of the tax office.

Kinase whose source, assay method, substrate, first antibody, second antibody, reaction buffer, reaction volume, ATP concentration and response time are as follows.ATM and ATR: total length recombined human kinases, 293T cell, enzyme-linked immunosorbent assay (ELISA), GST-p53 (aa1-99), anti--p53-phosphorylation Ser15, the anti-rabbit igg of horseradish peroxidase (HRP) labelling, 1xMg/Mn kinase buffer liquid (20mM Hepes-KOH (pH7.5), 1mM DTT, 80ug/ml BSA, 10mM MgCl ₂, 10mM MnCl ₂), 50ul, 100uM and 60 minutes.Chk1, Chk2 and c-Tak1: total length recombined human kinases, SF-9 cell (Chk1), total length recombined human kinases, escherichia coli (E.Coli) cells (Chk2) and total length recombined human kinases, anti-mice IgG, 1 * Mg kinase buffer liquid (20mM Hepes-KOH (pH7.5) of SF-9 cell (c-Tak1), ELISA, GST-Cdc25C (aa167-267), anti--Cdc25C-phosphorylation Ser216, HRP-labelling, 1mM DTT, 80ug/ml BSA, 10mM MgCl ₂), 50ul, 50uM and 60 minutes.PLK-1: people's total length GST fusant, the anti-mice IgG of escherichia coli, ELISA, gst fusion protein Y, anti-phosphorylation Ser/Thr monoclonal antibody, HRP-labelling, 1 * Mg kinase buffer liquid, 30ul, 50uM and 60 minutes.Weel: people's total length reorganization kinases GST fusant, the anti-rabbit igg of escherichia coli, ELISA, anti--Cdc2-phosphorylation Tyr15, HRP-labelling, 1 * Mg kinase buffer liquid, 50ul, 100uM and 60 minutes.DNA-PK: people's purification, the anti-rabbit igg of HeLa cell, ELISA, GST-p53 (aa 1-99), anti--p53-phosphorylation Ser15, HRP-labelling, 1 * Mg kinase buffer liquid, 50ul, 100uM and 60 minutes.Cdk2-cyclin A, Cdc2-cell periodic protein B, Cdk2-cyclin E and Cdk4-cyclin D1: total length recombinant human protein, the resisting of SF-9 cell, sandwich ELISA, anti--RB-phosphorylation Thr356, Ser612, Thr356 and Thr356 (difference), HRP-labelling-RB mouse monoclonal antibody, 1 * Cdk/ cyclin reaction buffer (50mM Hepes-KOH (pH7.5), 1mM EGTA, 1mM DTT, 200ug/ml BSA, 15mM MgCl ₂, 0.02%Tween-20,10% glycerol), 50ul, 100uM and 30 minutes.Cdk5-p25: people's total length reorganization kinases GST fusant, escherichia coli, glass filter disc are captured test (use γ-32ATP), histone h1,1 * Mg kinase buffer liquid, 30ul, 25uM and 60 minutes.PKA: the people catalytic subunit that recombinates, escherichia coli, ELISA, PS peptide, biotinylation mouse monoclonal antibody 2B9, HRP Succ-PEG-DSPE, 1 * PKA reaction buffer (20mM Tris HCl (pH7.0), 3mM MgCl ₂), 50ul, 100uM and 30 minutes.PKC: purification of rat, rat brain, ELISA, PS peptide, biotinylation mouse monoclonal antibody 2B9, HRP put together Succ-PEG-DSPE, 1 * PKC buffer (20mMTris HCl (pH7.0), 3mM MgCl ₂, 2mM CaCl ₂, the 50ug/ml Phosphatidylserine), 50ul, 100uM and 30 minutes.

All cultivations are all carried out at 30 ℃.The following phosphorylation inhibition analysis that carries out.Various kinases, ATP and substrate in above specified buffer with or do not cultivate the specified times down at 30 ℃ with CBP501 (0.5,5,50uM).Detected with ELISA or RIA as mentioned above by the substrate of phosphorylation.Substrate phosphorylation percentage ratio in the reaction is mapped to CBP501 concentration.The phosphorylated substrate amount of each kinase reaction of no CBP501 is appointed as 100%.

Embodiment 4

Present embodiment shows the inhibitory action (Fig. 2) of CBP501 to yeast AH109 growth on the YAPD flat board.

The yeast AH109 that is in exponential phase in the fluid medium (YAPD) is diluted 1-10 doubly with warm liquid YAPD culture medium (adding or do not add the CBP501 and/or the amphotericin B of prescribed dose).After cultivating 1 hour under 30 ℃, pour complete soln into the YAPD agarose plate.Then flat board was cultivated 3 days, to sample take pictures (Fig. 2).

Embodiment 5

Present embodiment shows the growth inhibited effect of CBP501 to Candida albicans (Candida albicans), Candidaglabrata, neogenesis cryptococcus (Cryptococcus neoformans) and Trichophyton mentagrophytes (Trichophyton mentagroohytes).

Candida albicans is available from ATCC (ATCC 10231), 37 ℃ of cultivations in liquid Sha Shi (Sabouraud) culture medium.Handled back 1 day in inoculation and with 0.03,0.1,0.3,1,3,10,30,100 μ g/mlCBP501, measure turbidity.Candida glabrata is available from ATCC (ATCC36583), 28 ℃ of cultivations in the liquid sabouraud culture medium.Handled back 2 days in inoculation and with 0.03,0.1,0.3,1,3,10,30,100 μ g/ml CBP501, measure turbidity.Neogenesis cryptococcus is available from ATCC (ATCC 24067), 37 ℃ of cultivations in the liquid sabouraud culture medium.Handled back 2 days in inoculation and with 0.03,0.1,0.3,1,3,10,30,100 μ g/ml CBP501, measure turbidity.Trichophyton mentagrophytes is available from ATCC (ATCC 9533), 28 ℃ of cultivations in potato glucose gravy.Handled back 3 days in inoculation and with 0.03,0.1,0.3,1,3,10,30,100 μ g/mlCBP501, measure turbidity.Minimum growth inhibitory concentration is defined as the Cmin (table 2) of CBP501 under the situation that turbidity does not increase.

Table 2:CBP501 is to the antifungal activity of various funguses

	The MIC of CBP501 ^*
	The MIC of CBP501 ^*	Candida albicans	100μg/ml
Candida glabrata	30μg/ml	Candida albicans	100μg/ml
Candida glabrata	30μg/ml	Neogenesis cryptococcus	1μg/ml
Trichophyton mentagrophytes	100μg/ml	Neogenesis cryptococcus	1μg/ml

MIC ^*=minimal inhibitory concentration

Claims

1. method that suppresses or reduce fungal infection or conk, described method comprises makes the object of fungus or contact fungus contact with a certain amount of peptide or peptide mimics, and described peptide or peptide mimics comprise and have 90% or higher conforming sequence with undefined sequence:

(i) P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in spatial aminoacid of similar side chain or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 be d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), d-or 1-Bpa, d-or 1-Phe ₄NO ₂, have any aminoacid that has one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline or a quinazoline group in spatial aminoacid of similar side chain or the side chain; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical; P6 is d-or 1-Bpa, d-or 1-Phe ₄NO ₂, any aminoacid and d-or 1-Tyr, any aminoacid and d-or 1-Phe, any aminoacid or do not exist;

(ii) or its prodrug, described amount is enough to suppress or reduce fungal infection or conk.

2. the process of claim 1 wherein that described peptide or peptide mimics comprise arbitrary sequence that table 1 is listed, and described peptide or peptide mimics has antifungal activity.

3. the method for claim 1, described method further comprise to be made fungus or object contact or is exposed to nucleic acid damaging agents or the nucleic acid damaging treatment.

4. the process of claim 1 wherein that described fungus or object come across in the object.

5. the process of claim 1 wherein that described fungus comprises yeast, mycete or slime mould.

6. the method for claim 5, wherein said yeast comprises candidiasis (Candida) or yeast (Saccharomyces).

7. the process of claim 1 wherein that described fungus or object come across in the environment, in residential area, shopping centre, industrial occupancy or the community, perhaps in agricultural or the gardening zone.

8. method that suppresses or reduce the fungal contamination of object or organism, described method comprises makes object or organism contact with a certain amount of chemical compound of peptide or peptide mimics that comprises, described peptide or peptide mimics comprise and have 90% or higher conforming sequence with undefined sequence:

(ii) or its prodrug, described amount is enough to suppress or reduce the pollution of object or organism.

9. the method for claim 8, described method further comprise to be made object or organism contact or is exposed to nucleic acid damaging agents or the nucleic acid damaging treatment.

10. the method for claim 9, wherein said organism comprises cell.

11. the method for claim 10, wherein said cell is a cultured cell.

12. the method for claim 9, wherein said organism is a human subjects.

13. the method for claim 9, wherein said organism is a plant.

14. the method for claim 8, wherein said object is an xenobiotic.

15. the method for claim 8, wherein said object are inorganic material or organic material.

16. the method for claim 8, wherein said fungus comprises yeast, mycete or slime mould.

17. method for the treatment of conk or fungal infection, described method comprises a certain amount of chemical compound of object that has conk or fungal infection or have this risk, and described chemical compound comprises and has 90% or higher conforming sequence with undefined sequence:

(ii) or its prodrug, described amount can effectively be treated conk or fungal infection.

18. the method for claim 17, wherein said peptide or peptide mimics comprise arbitrary sequence that table 1 is listed, and described peptide or peptide mimics have antifungal activity.

19. the method for claim 17, wherein said chemical compound part, zone or whole body administration.

20. the method for claim 17, wherein said chemical compound in fungus contact, pollute, growth or infect before, basically simultaneously or administration afterwards.

21. the method for claim 17, wherein said compound administration is in skin, toe, fingernail, hair or mucous membrane tissue.

22. the method for claim 17, wherein said conk or fungal infection to small part comes across skin, toe, fingernail, hair or mucous membrane tissue.

23. the method for claim 22, wherein mucous membrane tissue is selected from gastrointestinal tract, oral cavity, lung, bronchial, nasal meatus and nasal sinuses, genitourinary tract and vagina.

24. the method for claim 17, wherein said conk or fungal infection comprise yeast or mycete.

25. the method for claim 17, wherein said conk or fungal infection are selected from dermatophytes (dermatophytes), Blastomyces coccidioides (Coccidioides immitis), Histoplasma capsulatum (Histoplasma capsulatum), Candida albicans (Candida albicans) and Aspergillus fumigatus (Aspergillus fumigatus).

26. the method for claim 17, wherein said conk or fungal infection cause tinea unguium, tinea cruris or tinea pedis, paracoccidioidomycosis, blastomycosis, mucormycosis, cryptococcosis, coccidioidomycosis, histoplasmosis, candidiasis and aspergillosis.

27. the method for claim 17, wherein said treatment cause the object disease to take a turn for the better.

28. the method for claim 27, wherein said improvement comprise reduce stimulate, itch, inflammation, inflammation, urticaria, serosity are oozed out, pruritus, ejection are excessive, variable color, headache and fatigue.

29. the method for claim 27, wherein said improvement comprise susceptibility or the retransmission rate that reduces conk or fungal infection.

30. the method for claim 27, wherein said improvement comprise deterioration or the development that suppresses the object disease.

31. further comprising, the method for claim 27, described method give object nucleic acid damaging agents, nucleic acid damaging treatment, antifungal or antifungal therapy.

32. the method for claim 31, wherein said medicament or treatment comprise medicine.

33. the method for claim 32, wherein said medicine comprises chemotherapeutics.

34. the method for claim 32, wherein said medicine have antifungal activity or antifungal function.

35. the method for claim 32, wherein said medicine are systemic medication or locality medicine.

36. the method for claim 32, wherein said medicine is selected from following chemical classes: allylamine, pyrroles, polyenoid, pyrimidine, tetraene, thiocarbamate, sulfonamide, glucosan synthetic inhibitor and benzoic acid compounds.

37. the method for claim 32, wherein said medicine is selected from amrolfine, butenafine, naftifine, terbinafine, ketoconazole, fluconazol, elubiol, econazole, econaxole, itraconazole, isoconazole, imidazoles, miconazole, sulconazole, clotrimazole, enilconazole, oxiconazole, tioconazole, terconazole (triaconazole), butoconazole, thiabendazole, voriconazole, Saperconazole, Sertaconazole, fenticonazole, posaconazole, bifonazole, flutrimazole, nystatin, natamycin, amphotericin B, flucytosine, natamycin, tolnaftate, mafenide, dapsone, Caspofungin, actofunicone, griseofulvin, potassium iodide, Gentian Violet, ciclopirox, ciclopirox olamine, haloprogin, undecylenate salt, silver sulfadiazine, undecylenic acid, undecylenic acid alkanolamide and carbolfuchsin.

38. the method for claim 32, wherein said medicine comprise 5-fluorouracil (5-FU), rebecca mycin, amycin (ADR), bleomycin (Bleo), peplomycin, cis-platinum derivative, camptothecine (CPT) and their prodrug.

39. method for the treatment of conk, pollution or infection, described method comprise make have conk, pollution or infection or exist plant, plant part or the seed of this risk to contact with a certain amount of sequence, described sequence with have 90% or higher concordance with undefined sequence:

(ii) or its prodrug, described amount can effectively be treated conk, pollution or infection.

40. the method for claim 39, wherein said peptide or peptide mimics comprise arbitrary sequence that table 1 is listed, and described peptide or peptide mimics have antifungal activity.

41. the method for claim 39, wherein said plant, plant part or seed are in local, zone or systematically contact with described sequence.

42. the method for claim 39, wherein said plant, plant part or seed at conk, pollution or before infecting, basically simultaneously or contact with described sequence afterwards.

43. the method for claim 39, wherein said plant part comprises leaf, stem, root, flower, seed, trunk or branch.

44. the method for claim 39, wherein said conk, pollution or infect to small part comes across on leaf, stem, root, flower, seed, trunk or the branch.

45. the method for claim 39, wherein said conk, pollution or infection are caused by yeast, mycete or slime mould.

46. the method for claim 39, wherein said conk, pollution or infection are selected from melasma, anthrax, ripe spot, sooty mould, septoria musiva leaf spot, Cercospora leaf spot, rust, downy mildew, brown rot, brown spot, smut, Verrucosis, dead arm disease, ball chamber bacterium leaf spot, Flos Rosae Rugosae melasma, flower gangrenosis, septoria musiva dead leaf disease, early blight and late blight, leaf mold, anthrax, ring spot, dollar spot, the leaf blight of corn, pears alternaria and leasporaspot.

47. the method for claim 39, wherein said treatment cause reducing, reduce or suppress conk, pollution, existence or infection.

48. the method for claim 39, wherein said treatment cause reducing the susceptibility or the retransmission rate of conk, pollution or infection.

49. the method for claim 39, wherein said treatment cause suppressing the deterioration or the development of conk, pollution or infection.

50. the method for claim 39, described method further comprise plant, plant part or seed are contacted with nucleic acid damaging agents, nucleic acid damaging treatment, antifungal or antifungal therapy.

51. the method for claim 50, wherein said medicament or treatment comprise medicine.

52. the method for claim 51, wherein said medicine comprises chemotherapeutics.

53. the method for claim 51, wherein said medicine have antifungal activity or antifungal function.

54. the method for claim 51, wherein said medicine are selected from yellow grand, the Mancozeb of Banner Maxx, CompassCleary ' s, triforine, Immunox, zineb, sulphur ammonia, nitrile bacterium azoles, holder and pounce on clean, captan, thiram, carboxin, metalaxyl, PCNB, CGA-173506, thiabendazole, cuprio antifungal, sulfur-containing compound, citrus oils and bacillus subtilis (Bacillus subtilis).

55. the method for claim 51, wherein said medicine comprise 5-fluorouracil (5-FU), rebecca mycin, amycin (ADR), bleomycin (Bleo), peplomycin, cis-platinum derivative, camptothecine (CPT) and their prodrug.

56. the method for claim 50, wherein said plant, plant part or seed come across in the environment, in the industrial occupancy, community, residential area, shopping centre, perhaps in agricultural or gardening zone.

57. a compositions, described compositions comprise antifungal therapy or antifungal and peptide or peptide mimics, the sequence that described peptide or peptide mimics comprise with have 90% or higher concordance with undefined sequence:

(i) P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), have any aminoacid that has one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline or a quinazoline group in spatial aminoacid of similar side chain or the side chain; P2 be d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), d-or 1-Bpa, d-or 1-Phe ₄NO ₂, have any aminoacid that has one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline or a quinazoline group in spatial aminoacid of similar side chain or the side chain; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical; P6 is d-or 1-Bpa, d-or 1-Phe ₄NO ₂, any aminoacid and d-or 1-Tyr, any aminoacid and d-or 1-Phe, any aminoacid or do not exist;

(ii) or its prodrug.

58. a compositions, described compositions comprise antiinflammatory, antimicrobial or anti-inflammatory treatment or medicament and peptide or peptide mimics, the sequence that described peptide or peptide mimics comprise with have 90% or higher concordance with undefined sequence:

(i) P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in spatial aminoacid of similar side chain or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 be d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), d-or 1-Bpa, d-or 1-Phe ₄NO ₂, have any aminoacid that has one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline or a quinazoline group in spatial aminoacid of similar side chain or the side chain; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical; P6 is d-or 1-Bpa, d-or l-Phe ₄NO ₂, any aminoacid and d-or 1-Tyr, any aminoacid and d-or 1-Phe, any aminoacid or do not exist;

(ii) or its prodrug.

59. an evaluation has the method for the chemical compound of antifungal activity, described method comprises:

(i) chemical compound at the elimination or the inhibition G2 outpost of the tax office is contacted with fungus;

(ii) make fungus cultivate with described chemical compound;

(iii) measure existence, growth or the propagation of fungus, the existence of fungus when wherein chemical compound exists, growth or propagation reduce this chemical compound of confirmation and have antifungal activity.

60. a screening has the method for the chemical compound of antifungal activity, described method comprises:

(ii) make fungus cultivate with described chemical compound;

(iii) measure existence, growth or the propagation of fungus.

61. an evaluation has the method for the peptide or the peptide mimics of antifungal activity, described method comprises:

(i) peptide or peptide mimics are contacted with fungus;

(ii) make fungus cultivate with peptide or peptide mimics;

(iii) measure existence, growth or the propagation of fungus, the existence of fungus when wherein peptide or peptide mimics exist, growth or propagation reduce this peptide of confirmation or peptide mimics has antifungal activity;

(iv) wherein peptide or peptide mimics comprise:

P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in spatial aminoacid of similar side chain or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 be d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), d-or 1-Bpa, d-or 1-Phe ₄NO ₂, have any aminoacid that has one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole, pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline or a quinazoline group in spatial aminoacid of similar side chain or the side chain; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical; P6 is d-or 1-Bpa, d-or 1-Phe ₄NO ₂, any aminoacid and d-or 1-Tyr, any aminoacid and d-or 1-Phe, any aminoacid or do not exist; Or its prodrug.

62. a screening has the method for the peptide or the peptide mimics of antifungal activity, described method comprises:

(i) peptide or peptide mimics are contacted with fungus;

(ii) make fungus cultivate with peptide or peptide mimics;

(iii) measure existence, growth or the propagation of fungus;

(iv) wherein peptide or peptide mimics comprise:

P1, P2, P3, P4, P5, P6 or P6, P5, P4, P3, P2, P1; Wherein P1 is d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in spatial aminoacid of similar side chain or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P2 be d-or 1-Cha, d-or 1-Nal (2), d-or 1-(Phe-2,3,4,5,6-F), d-or 1-(Phe-3,4,5F), d-or 1-(Phe-4CF3), d-or 1-Bpa, d-or 1-Phe ₄NO ₂, have have one or two aryl, piperidines, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group or indole in spatial aminoacid of similar side chain or the side chain, any aminoacid of pentalene, indenes, naphthalene, benzofuran, benzothiophene, quinoline, indoline, benzodihydropyran, quinoxaline, quinazoline group; P3, P4, P5 are any aminoacid, and perhaps one or more among P3, P4, the P5 are simple carbochains, make the distance of the distance of P2 and P6 when respectively doing for oneself aminoacid as P3, P4, P5 be close to identical; P6 is d-or 1-Bpa, d-or 1-Phe ₄NO ₂, any aminoacid and d-or 1-Tyr, any aminoacid and d-or 1-Phe, any aminoacid or do not exist; Or its prodrug.