WO2017188498A1 - 병원균에 대한 항생활성을 갖는 펩타이드 및 이를 포함하는 항생 펩타이드 조성물 - Google Patents
병원균에 대한 항생활성을 갖는 펩타이드 및 이를 포함하는 항생 펩타이드 조성물 Download PDFInfo
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- WO2017188498A1 WO2017188498A1 PCT/KR2016/005513 KR2016005513W WO2017188498A1 WO 2017188498 A1 WO2017188498 A1 WO 2017188498A1 KR 2016005513 W KR2016005513 W KR 2016005513W WO 2017188498 A1 WO2017188498 A1 WO 2017188498A1
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- peptide
- antibiotic
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a peptide having an anti-biological activity against a pathogen and an antibiotic peptide composition comprising the same, and more particularly, LPcin I which significantly increases the antibiotic ability by deleting and / or replacing some amino acids in an LPcin I peptide having antibiotic activity.
- the present invention relates to a peptide having anti-biological activity against a pathogen derived from a peptide and an antibiotic peptide composition comprising the same.
- the merganine of the peptide antibiotic is a peptide having a 23 amino acid composition isolated from the amphibian epidermis (Zasloff, M., Proc. Natl. Acad. Sci. USA, 84, pp5449-5453, 1987), as well as pathogens It has also been reported to work on lung cancer cells.
- most of the antibiotic peptides specifically act on the cells to kill the target cells quickly, and most of them show an active spectrum in a wide range (Park, CB et al., Biochem. Biophys. Res. Comm., 218, pp 408-). 413, 1996).
- the antibiotic peptides first, have a strong antibiotic against a wide range of microorganisms, second, the host cell acts only on pathogens invading from the outside without destroying, acting as an antibiotic harmless to the human body, and third, the induction of resistance of microorganisms It is unlikely to be a problem with conventional antibiotics, and its activity mechanism is completely different. Therefore, it is less likely to induce resistance. Fourth, since there is no secondary modification such as glycosylation, it can be mass-produced through genetic manipulation. Fifth, since it has a strong physicochemical stability, such as heat, acid or alkali, it has the advantage that the industrial utility in the pharmaceutical and food fields is very large.
- antibiotic peptides The mechanism of action of antibiotic peptides reported to date is largely classified into two categories. First, most antibiotic peptides have a mechanism of action that increases the permeability of bacterial cell membranes, disrupting membrane potential and stopping cell metabolism. Second, a few other antibiotic peptides exhibit a potent mechanism of penetration into fungal cells and binding to DNA or RNA to inhibit transcription or translation.
- Structural factors known to be important for the activity of these antibiotic peptides include: first, amphipathic helix, second, distribution of residues that stabilize the helix, third, distribution of basic residues, and fourth. , The distribution of hydrophobic residues, fifth, the interaction between charged residues and the dipole of the helical structure, and sixth, the salt bridge between the oppositely charged residues.
- lactoporic acid present in cow's milk is a cationic, amphiphilic peptide having 23 amino acid residues and is located at the carboxy terminal 113-135 region of PP3.
- LPcin-I inhibits the growth of both Gram-positive and Gram-negative bacteria but shows no hemolysis at concentrations below 200 ⁇ M.
- LPcin-II corresponding to amino acids 119-135 of PP3, is known to have no antibiotic function.
- LPcin-I known to have antimicrobial activity, requires commercial development of antibiotic peptides consisting of shorter amino acid sequences in order to commercialize them.
- the present invention has been made to solve the above-mentioned problems, the first problem to be solved of the present invention, compared to the wild-type lactoporicin (LPcin-I) antibiotic peptide consisting of 23 amino acids, while the number of amino acid sequence is less antibiotic It is to provide a peptide having anti-biosis against markedly improved pathogens.
- LPcin-I lactoporicin
- the second object of the present invention is to provide an antibiotic composition comprising the antibiotic peptide of the present invention as an active ingredient.
- the present invention provides a peptide represented by the following general formula (I) having anti-bioactivity against pathogens.
- X 1 is I or W; If X 1 is I, X 2 is Y, and if X 1 is W, X 2 is W; X 3 is S or K; X 4 is L or K; X 5 is S or K.
- the present invention also provides the use of a peptide represented by the above sequence [Formula I] having antibiosis against pathogens.
- the peptide may be deleted X 3 X 4 FX 5 or FX 5 in formula (I).
- the peptide may comprise any one amino acid sequence selected from SEQ ID NO: 1 to 10.
- an antibiotic peptide composition comprising the antibiotic peptide of the present invention as an active ingredient.
- the present invention also provides the use of an antibiotic peptide composition comprising the antibiotic peptide as an active ingredient.
- the antibiotic activity of Staphylococcus aureus may be one or more of the antimicrobial to the bacteria selected from the group consisting of.
- the antibiotic peptide of the present invention and the antibiotic peptide composition comprising the same have a significantly higher antimicrobial activity against gram (+) and gram (-) strains compared to wild type LPcin-I having an antibiotic activity consisting of 23 amino acid sequences.
- the shorter the amino acid length in the drug delivery process the easier it is to be transported to where it is needed without being digested in vivo.
- the number of amino acids is smaller than that of wild type LPcin-I, it is easy to synthesize and is very advantageous in reducing the production cost.
- coli KCTC 1682 shows one Gram-positive bacterium ( Staphylococcus aureus ATCC 6538) and two Gram-negative bacteria ( Salmonella ATCC 19430 and Escherichia).
- coli KCTC 1682) is a photograph showing the results of anti-bioactivity test on three microorganisms consisting of.
- Figure 2 shows two Gram-positive bacteria ( Listeria innocua MC2 KCTC 3658 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria ( Pseudomonas aeruginosa ATCC27853, Salmonella ATCC 19430, Escherichia coli KCTC 1682) is a graph and chart measuring the minimum inhibitory concentration.
- lactoporic acid (LPcin-I) present in bovine milk is a cationic, amphiphilic peptide with 23 amino acid residues and is the carboxy terminus 113-135 region of PP3.
- LPcin-I inhibits the growth of both Gram-positive and Gram-negative bacteria but shows no hemolysis at concentrations below 200 ⁇ M.
- LPcin-I which is known to have antibiotic activity, is higher than wild type LPcin-I to commercialize it. There is an urgent need for the development of technology for producing antibiotic peptides consisting of shorter amino acid sequences in order to reduce antibiotic activity and manufacturing cost.
- the antibiotic peptide of the present invention and the antibiotic peptide composition comprising the same have significantly higher antimicrobial activity against gram (+) and gram (-) strains compared to wild type LPcin-I having an antibiotic activity consisting of 23 amino acid sequences. . Furthermore, since the number of amino acids is smaller than that of wild type LPcin-I, it is easy to synthesize and is very advantageous in reducing the production cost.
- X 1 is I or W; If X 1 is I, X 2 is Y, and if X 1 is W, X 2 is W; X 3 is S or K; X 4 is L or K; X 5 is S or K.
- Amino acid sequences used in the present invention are abbreviated as follows according to the IUPAC-IUB nomenclature.
- X 1 may be any of I, W, or non-polar amino acid, if X 1 is I and X 2 is Y, if X 1 X 2 is W is W.
- the nonpolar amino acid is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and proline (P).
- Polar amino acids are composed of serine (S), threonine (T), tyrosine (Y), asparagine (N) and glutamine (Q).
- Acidic amino acids are composed of aspartic acid (D), glutamic acid (E), and basic amino acids are composed of lysine (K), arginine (R), histidine (H).
- the peptide may be deleted X 3 X 4 FX 5 or FX 5 from the C-terminal.
- the antimicrobial peptides represented by SEQ ID NOs: 9 to 11 of the present invention are antimicrobial peptides deleted with FX 5
- the antimicrobial peptides represented by SEQ ID NO: 12 are antimicrobial peptides deleted with X 3 X 4 FX 5 .
- the antimicrobial peptides consisting of these SEQ ID NOS: 1 to 12 show significantly superior antimicrobial activity compared to wild type LPcin-I (SEQ ID NO: 13) (see Experimental Example 2).
- the peptide comprises any one amino acid sequence selected from SEQ ID NO: 1 to 10 to reduce the production cost and exhibit excellent antimicrobial activity (see Experimental Example 1).
- the antimicrobial peptides exhibiting excellent antimicrobial activity may be YK5 (SEQ ID NO: 3), YK8 (SEQ ID NO: 6) and YK11 peptide (SEQ ID NO: 9).
- the antimicrobial peptides YK5, YK8 and YK11 of the present invention are more economical because they can effectively inhibit the five strains mentioned above at lower concentrations compared to YK3.
- YK11 has an amino acid sequence of less than 2mer than YK3, there is an economic advantage to manufacture commercially.
- LPcin-I peptide consisting of 23 amino acids represented by SEQ ID NO: 13 can be produced through a conventional peptide synthesis method, specifically manufactured through an automatic peptide synthesizer, Recombinant expression vectors can be prepared and purified, and Korean Patent Application No. 2008-130593 relating to a method for synthesizing an LPcin-I antibiotic peptide through the recombinant expression vector is incorporated herein by reference.
- Fmoc (9-fluorenylmethoxycarbonyl) can be synthesized using the liquid phase solidification method of Merrifield using an amino group protective container (Merrifield, RB., J. Am. Chem. Soc., 85, 2149, 1963). ).
- the antibiotic peptide represented by the amino acid sequence of SEQ ID NO: 1 to 10 can be prepared by a conventional method as in the preparation of the antibiotic peptide of SEQ ID NO: 13.
- Antibiotic peptides of the present invention produced through this have high antibiotic activity against gram (+) strains, gram (-) strains, and two representative gram-positive bacteria ( Listeria) innocua MC2 KCTC 3658 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria ( Pseudomonas aeruginosa ATCC27853, Salmonella ATCC 19430, Escherichia coli KCTC 1682) has a high antimicrobial activity, but is not limited thereto.
- the present invention also relates to an antibiotic composition containing the antibiotic peptide as an active ingredient.
- Antibiotics containing the antibiotic peptide of the present invention as an active ingredient may be usefully used as additives of antibiotics, antifungals, food preservatives, cosmetic preservatives, trauma, eye drops and pharmaceutical preservatives.
- the antibiotic peptide of the present invention can be administered parenterally during clinical administration and can be used in the form of general pharmaceutical preparations.
- Antibiotic peptides of the present invention may be administered in a variety of parenteral formulations, which, when formulated, may be prepared using conventional diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like. have.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
- non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
- base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- antibiotic peptide of the present invention can be used in combination with a number of carriers (pharmaceutically acceptable carrier) such as physiological saline or organic solvent, carbohydrates such as glucose, sucrose or dextran, in order to increase the stability or absorption
- carriers pharmaceutically acceptable carrier
- Antioxidants such as ascorbic acid or glutathione, chelating agents, small molecule proteins or other stabilizers can be used as medicaments.
- the effective dose of the antibiotic peptide of the present invention is 0.1 to 3 mg / kg, preferably 0.5 to 1 mg / kg, and may be administered 1 to 3 times a day.
- Antibiotics containing the antibiotic peptide of the present invention as an active ingredient may be administered to a patient in a single dose by bolus form or by infusion for a relatively short period of time, and may be administered in multiple doses. dose) may be administered by a fractionated treatment protocol with long term administration.
- the effective dose of the antibiotic peptide of the present invention is determined in consideration of various factors such as the age and health condition of the patient, as well as the route of administration and the number of treatments of the drug, it is common knowledge in this field.
- anyone with A can determine the appropriate effective dose.
- the present invention provides a feed composition containing the antibiotic peptide of the present invention as an active ingredient.
- the effective dose may contain 0.01 to 100 mg per 1 kg of feed, and may be administered 1 to 3 times a day.
- SEQ ID NO: 11 is a wild-type LPcin-I antibiotic peptide having 23 amino acid sequences
- SEQ ID NOs 1 to 6 are antibiotic peptide sequences having 15 amino acid sequences
- SEQ ID NOs 7 to 9 are 13 amino acids
- SEQ ID NO: 10 is an antibiotic peptide sequence having 11 amino acid sequences.
- NKVKE WIKYL KSLFS One YK4 (15mer) NKVKE WWKWL KSLFS 2 YK5 (15mer) NKVKE WIKYL KSLFK 3 YK6 (15mer) NKVKE WIKYL KSKFS 4 YK7 (15mer) NKVKE WWKWL KSLFK 5 YK8 (15mer) NKVKE WIKYL KSKFK 6 YK9 (13mer) NKVKE WWKWL KSL 7 YK10 (13mer) NKVKE WIKYL KKL 8 YK11 (13mer) NKVKE WWKWL KKL 9 YK12 (11mer) NKVKE WWKWL K 10 LPcin-I (23mer) NTVKE TIKYL KSLFS HAFEV VKT 11
- Antibiotics were measured for 11 peptides 1 to 11 synthesized in Example 1 above. Specifically, antibiotic activity against microorganisms was performed using Brain heart infusion agar (BactoTM). Two Gram-positive bacteria ( Listeria innocua MC2 KCTC 3658 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria ( Pseudomonas aeruginosa ATCC27853, Salmonella ATCC 19430, Escherichia Five microorganisms of coli KCTC 1682) were based on agar disc diffusion tests. Inoculum was prepared by incubating the bacteria overnight at 37 ° C., 5 ml of 3.7% Brain heart infusion.
- the turbidity of the suspension was adjusted to a final concentration equal to 0.05 standard turbidity (1 x 108 CFU / mL) by spectrophotometer at 600 nm.
- 20 ml of Brain heart infusion agar was applied to a cell culture plate of ⁇ 90 mm.
- Agar plates were inoculated with 30 ul of bacterial suspension using a sterile spreader.
- Inoculated agar plates were dried at room temperature for 30 minutes.
- a sterile 6 mm filter paper (Whatman No. 1) was placed on the surface of the Agar plate and antibiotic peptides were dissolved in sterile at a concentration of 10 mM to inoculate 20 ul of solution onto the filter paper.
- the plates were incubated at 37 ° C. for 24 hours. After 24 hours, the sensitivity of the antibiotic peptides to the bacterial group was determined by the size and extent of inhibition of bacterial growth by measuring the growth inhibition diameter of the bacterial group around the filter paper. The measurement was repeated twice.
- FIG. 1 is a photograph showing the results of an agar disc diffusion test observed after 24 hours have elapsed. Among them, YK3 was carried out for comparison with a new peptide as a peptide having anti-life according to the method described in Korean Patent Application No. 2011-0049538.
- Cytotoxicity experiments were performed using the Cyto XTM cell viability assay kit (LPS solution) assay.
- 96-well cell culture plates were roasted from corning and mammalian cell lines were purchased from ATCC.
- Cyto XTM cell visualization kit was also purchased from LPS solution.
- cryopreserved cells were thawed and cultured in DMEM or RPMI1640 medium containing 10% FBS, and then passaged at 2-3 days intervals when the cell density reached 80-90%. .
- the cells were detached by treatment with Trypsin-EDTA for the experiment, and then dispensed into 96-well so that the number of cells was 10,000. Then, it was incubated for 24 hours in 37 degreeC CO2 incubator.
- the prepared peptide was diluted in DMSO to prepare a concentration of 10, 1, 0.1, 0.01, 0.001 mM, and then diluted 1/100 times by adding 1 ⁇ l of DMSO or prepared peptide to each well to be treated.
- IC50 values in various mammalian cell lines for the four peptides are shown in Table 2 below. If the IC50 by four peptides is 10 ⁇ M or more in each cell line, it is determined that there is no general cytotoxicity. The following four peptides were confirmed to be safe for general cytotoxicity.
- the YK3 peptide showed IC50 values at 56.2 uM, while the YK5, YK8 and YK11 peptides had IC50 values of 57.0, 71.9 and 86.8 uM, which were higher.
- YK5, YK8 and YK11 peptides were found to have lower cytotoxicity than YK3 peptides.
- Antimicrobial assays were performed by measuring minimal inhibitory concentration (MIC) values using a standard broth microdilution method.
- Antimicrobial activity of each peptide is the two gram-positive bacteria (Listeria innocua MC2 KCTC 3658 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria ( Pseudomonas aeruginosa ATCC27853, Salmonella ATCC 19430, Escherichia coli KCTC 1682). These five bacteria were prepared in 50 ⁇ l, and then mixed in 5 ml of 3.7% BHI and incubated at 37 ° C. and 240 rpm for one day.
- MIC minimal inhibitory concentration
- the cultured bacteria were mixed with 5 ml of 3.7% BHI and incubated at 37 ° C. and 240 rpm for 2 hours.
- the cultured bacteria were diluted with 0.037% BHI solution and prepared at a concentration of 1 ⁇ 108 CFU / mL.
- the dissolved synthetic peptides were diluted twice in BHIB in 96 well-plates. 5 ⁇ l of each of the bacteria prepared by diluting with 100 ⁇ l of various concentrations of the synthetic peptide was mixed in a 96 well-plate (microreader plate), followed by shaking culture at 37 ° C. for 12 hours. After incubation, the change in absorbance at 600 nm was measured using Microplate Reader Multiskan FC (Thermo scientific, Waltham, MA, USA), and the range of MIC was set to the lowest concentration of peptides at which bacterial growth began to be inhibited. Half maximal Inhibitory Concentration (IC50), in which the growth of bacteria is 50% compared with the control group, was confirmed. As a solvent control, 100 ⁇ l of BHIB solution containing no peptide was mixed with 5 ⁇ l of bacteria, and the same method as the experimental group was performed. This experiment was repeated three times for the accuracy of the experiment.
- IC50 Half maximal Inhibitory Concentration
- the antibiotic peptide prepared in the present invention exhibits excellent antimicrobial activity in both Gram-positive bacteria and Gram-negative bacteria and is safe for humans. And eye drops, and the like.
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Abstract
Description
펩타이드 명칭 | 아미노산 서열 | 서열번호 |
YK3 (15mer) | NKVKE WIKYL KSLFS | 1 |
YK4 (15mer) | NKVKE WWKWL KSLFS | 2 |
YK5 (15mer) | NKVKE WIKYL KSLFK | 3 |
YK6 (15mer) | NKVKE WIKYL KSKFS | 4 |
YK7 (15mer) | NKVKE WWKWL KSLFK | 5 |
YK8 (15mer) | NKVKE WIKYL KSKFK | 6 |
YK9 (13mer) | NKVKE WWKWL KSL | 7 |
YK10 (13mer) | NKVKE WIKYL KKL | 8 |
YK11 (13mer) | NKVKE WWKWL KKL | 9 |
YK12 (11mer) | NKVKE WWKWL K | 10 |
LPcin-I (23mer) | NTVKE TIKYL KSLFS HAFEV VKT | 11 |
화합물 | IC50(μM) | ||||
VERO | HFL-1 | L929 | NIH3T3 | CHO-K1 | |
YK3 | 99.1 | 94.0 | >100 | 76.0 | 56.2 |
YK5 | >100 | >100 | >100 | >100 | 57.0 |
YK8 | >100 | >100 | >100 | >100 | 71.9 |
YK11 | 83.7 | >100 | >100 | 96.6 | 86.8 |
펩타이드 | 아미노산 서열 | 분자량 | 서열번호 | |
15 mer | YK3 | NKVKE WIKYL KSLFS | 1883.2 | 1 |
YK5 | NKVKE WIKYL KSLFK | 1883.2 | 3 | |
YK8 | NKVKE WIKYL KSKFK | 1939.2 | 6 | |
13 mer | YK11 | NKVKE WWKWL KKL | 1786.2 | 9 |
Claims (7)
- 병원균에 대한 항생활성을 갖는 하기 서열 [일반식 Ⅰ]로 표현되는 펩타이드:[일반식 Ⅰ][(N-말단)-N K V K E W X1 K X2 L K X3 X4 F X5-(C-말단)]여기에서, X1은 I 또는 W이고; X1이 I이면, X2는 Y이고, X1이 W이면, X2는W이며; X3는 S 또는 K이고; X4는 L 또는 K이며; X5는 S 또는 K임.
- 제1항에 있어서, 상기 펩타이드는 일반식Ⅰ에서 X3 X4 F X5 또는 F X5가 결실된 것을 특징으로 하는 펩타이드.
- 제1항에 있어서, 상기 펩타이드는 서열번호 1 내지 10 중에서 선택된 어느 하나의 아미노산 서열을 갖는 것을 특징으로 하는 펩타이드.
- 제1항 내지 제3항 중 어느 한 항의 항생 펩타이드를 유효성분으로 포함하는 항생 펩타이드 조성물.
- 제4항에 있어서, 상기 항생 활성은 포도상구균(Staphylococcus aureus), 살모넬라균(Salmonella), 리스테리아 이노쿠아(Listeria innocua), 녹농균(Pseudomonas aeruginosa), 및 대장균(Escherichia coli)으로 이루어지는 군에서 선택되는 어느 하나 이상의 균에 대한 항생활성인 것을 특징으로 하는 항생 펩타이드 조성물.
- 병원균에 대한 항생활성을 갖는 하기 서열 [일반식 Ⅰ]로 표현되는 펩타이드의 용도:[일반식 Ⅰ][(N-말단)-N K V K E W X1 K X2 L K X3 X4 F X5-(C-말단)]여기에서, X1은 I 또는 W이고; X1이 I이면, X2는 Y이고, X1이 W이면, X2는W이며; X3는 S 또는 K이고; X4는 L 또는 K이며; X5는 S 또는 K임.
- 제 6항의 항생 펩타이드를 유효성분으로 포함하는 항생 펩타이드 조성물의 용도.
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KR20100071769A (ko) * | 2008-12-19 | 2010-06-29 | 한국외국어대학교 연구산학협력단 | LPcin-Ⅰ펩타이드 또는 LPcin-Ⅱ 펩타이드를 포함하는 재조합 발현벡터 및 이를 이용한 펩타이드의 대량생산방법 |
KR20120131399A (ko) * | 2011-05-25 | 2012-12-05 | 한국외국어대학교 연구산학협력단 | 미생물에 대한 항생활성을 갖는 펩타이드 및 이를 포함하는 항생 펩타이드 조성물 |
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Also Published As
Publication number | Publication date |
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JP6820251B2 (ja) | 2021-01-27 |
JP2019523211A (ja) | 2019-08-22 |
US10150795B2 (en) | 2018-12-11 |
KR20170122026A (ko) | 2017-11-03 |
US20180170965A1 (en) | 2018-06-21 |
KR101847051B1 (ko) | 2018-04-09 |
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