WO1980000789A1 - Antibacterial peptide - Google Patents
Antibacterial peptide Download PDFInfo
- Publication number
- WO1980000789A1 WO1980000789A1 PCT/US1979/000752 US7900752W WO8000789A1 WO 1980000789 A1 WO1980000789 A1 WO 1980000789A1 US 7900752 W US7900752 W US 7900752W WO 8000789 A1 WO8000789 A1 WO 8000789A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluorine
- chlorine
- group
- peptide
- composition
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
Definitions
- aminoacid is in the D-configuration
- X is chlorine or fluorine
- R is the acyl moiety of an ⁇ -aminoacid in the L-configuration
- the ⁇ -amino group may carry a fatty acid acyl group or an aminolower-alkyl acyl group or a loweralkyl group, or the corresponding loweralkyl esters of said dipeptide, or nontoxic acid addition salts thereof, are useful antibacterials; they also represent powerful synergists for D-cycloserine and other antibiotics.
- R particulary represents the known, protein-derived aminoacids, including glycine which, of course, does not have a chiral center.
- the definition also includes other aminoacids where the amino group is attached to the 2- or ⁇ -position of the acid.
- the amino group of substituent R may also carry an acyl group of a lower fatty acid or a loweralkyl group, primarily methyl, propyl, tert. butyl, acetyl, propionyl isobutyryl and the like.
- the protein-derived aminoacid may be represented by leucine, valine, norvaline, proline, serine, tyrosine, alanine, phenylalanine, threonine, methionine, glutamine, histidine, arginine, lysine and tryptophane.
- the new dipeptides have the unnatural seguence of an L-aminoacid (or glycine) coupled to D-haloalanine.
- L-D sequence is usually restricted to the cell wall components of microorganisms and its antibacterial activity is completely unexpected.
- the new dipeptide can easily be synthesized by coupling the known 3-fluoro- (or chloro-)-D-alanine with an active ester of a N ⁇ -protected glycine or an aminoacid in the L-configuration or a N ⁇ -alkyl homolog thereof.
- active esters the hydroxysuccinimide, pentachlorophenyl, 4-nitrophenyl, 2,4,5-trichlorophenyl, a fluorophenyl, N-hydroxyisobornyldicarboximide or similarly familiar esters of RCOO- can be used for the coupling reaction.
- N ⁇ - group and any other sensitive functional group in the aminoacid moiety represented by R above can be protected with the usual well-known groups that can subsequently be removed by a mild chemical reaction which does not affect the peptide bond formed.
- groups frequently used as temporary protection are the carbobenzoxy (hereinafter identifed as Z) or the tert. butoxycarbonyl for amino groups, particularly the N ⁇ - group, while benzyl or other moieties can be used to protect the hydroxy groups in serine, tyrosine or hydroxyproline or the imidazol group of histidine.
- Hydrogenation will remove said benzyl group after the peptide coupling has been effected and treatment with hydrobromic acid or hydrofluoric acid will remove other protective groups used by the skilled artisan, without cleaving the peptide bond.
- the free acid can be converted into the desired alkyl ester in known fashion and/or the N ⁇ - group can be acylated in known manner.
- the optical rotations were taken at 25°C. in IN HC1 at the concentrations given.
- Example 1 a) To a stirred solution of 214.2 mg. of ⁇ -fluoro-D-alanine and 420 mg. of sodium bicarbonate in 5 ml. of water was added a solution of 800.8 mg. of carbobenzoxy-L-alanine-N-hydroxysuccinimide ester in 5 ml. of 1 ,2-dimethoxyethane. After stirring overnight at ambient temperature, the solution was concentrated to a syrup under reduced pressure. The residue was dissolved in 10 ml. of water and acidified with lN-hydrochloric acid to precipitate 521 mg . of N-carbobenzoxy- L-alanyl- ⁇ -fluoro-D-alanine, m.p. 156-7°C.
- Example 2 By repeating the process of Example 1(a), but starting with 320 mg . of S-chloro-D-alanine hydrochloride and 588 mg. of sodium carbonate, 647 mg. of N- carbobenzoxy-L-alanyl- ⁇ -chloro-D-alanine was obtained; m.p. 168-70°C. b) A solution of 736 mg . of this protected peptide in 101 ml. of methanol containing one equivalent of HC1 was hydrogenated over 0.15 g. of 5% Pd on carbon. The catalyst was removed by filtration after the calculated amount of gaseous hydrogen had been absorbed. The catalyst was washed with methanol which was combined with the filtrate.
- Example 15 In an ice bath, 1.07 g. of ⁇ -fluoro-D-alanine in 20 ml. of methanol was treated with 1.1 ml. of S0C1 2 . The mixture was stirred two days at room temperature to give a clear solution. Solvent evaporation and trituration with ether gave 1.28 g. of the methyl ester of ⁇ F-D-Ala which melts at 130°C. with previous sintering above 110°C. A 630 mg. sample of this ester was treated as in Example 1(a), producing 738 mg . of amorphous Z-L-Ala- BF-D-Ala-OMe.
- Example 16 a A suspension of 512 mg. of the compound of Example 1 in 10 ml. of DMF was stirred with 1.0 ml. of acetic anhydride. After 90 minutes, the clear solution was diluted with water, evaporated to dryness and the residue placed on a chromatographic column containing AG-1-X2 (OAc), (an anionic exchange resin sold by the Dow Chemical Co.). Elution with 0.05 molar ammonium acetate gave 475 mg. of the ammonium salt of N ⁇ -Ac-L-Ala; [ ⁇ ] D - 21.2° (c, 1.3).
- OAc AG-1-X2
- Example 17 In analogy with Example 1, the N ⁇ -carbo- benzoxy derivative of L- ⁇ -aminobutyric acid was coupled to ⁇ F-D-Ala, followed by the usual deprotection reaction to give L- ⁇ NH 2 -But- ⁇ F-D-Ala melting at 182°C.(d). The mentioned intermediate showed a m.p. of 169-70°C; [ ⁇ J D + 66° (c, 0.5).
- Example 18 Using ⁇ C1-D-Ala in the procedure of Example 17 gave a N ⁇ -protected intermediate melting at 166-8°C.
- Example 19 In a manner similar to Example 1(a), N ⁇ -tert-butyloxycarbonyl-L-norvaline was coupled to ⁇ F-D-Ala to yield the t-BOC-L-norvalyl- ⁇ F-D-Ala. It was then deprotected as follows:
- a suspension of 2.34 g. of D,L- ⁇ -amino-octanoic acid in 30 ml. of water containing 2.52 g. of NaHCO 3 was stirred in an ice bath with a solution of 4.38 g. of carbobenzoxy-N-hydroxysuccinimidyl carbonate in 30 ml. of 1 ,2-dimethoxyethane. After 3 hours, the temperature was allowed to adjust to room temperature and stirring was continued for three days. The resulting solution was cooled in an ice bath and acidified with 2NH 6 to produce 2.1 g. of the desired protected amino acid; m.p. 89-92°C.
- the active N-hydroxysuccinimide ester of the above was made in known fashion; it melts at 90°- 5°C. This material was coupled to ⁇ F-D-Ala in the fashion shown in the preceding examples.
- the N ⁇ -protected dipeptide melts at 116-22°C, while the desired D,L- ⁇ -amino-octanoyl- ⁇ F-D-Ala melts at 185-92°C.; [ ⁇ ] D + 19° (c 0.5).
- Other compounds of the above general description can easily be made by repeating Example 1(a) but using the succinimide esters of other N ⁇ -protected amino acids.
- ester is that of isoleucine or ⁇ -aminocaproic acid
- R represents L-isoleucyl or L- ⁇ -amino-aminocaproyl
- other amino acid esters carrying protected additional functional groups can be employed to make the dipeptides of the current invention.
- the L-threonyl-, L-tryptophyl- and L-tyrosyl- ⁇ -fluoro (or chloro)-D-alanines can be made by the above route.
- the functional groups, where present can be temporarily protected in known fashion by benzyl, carbobenzyloxy, tert. butyl or othe protective groups commonly used in the peptide art.
- the functional groups, where present can be temporarily protected in known fashion by benzyl, carbobenzyloxy, tert. butyl or othe protective groups commonly used in the peptide art.
- the compounds of the current inven tion allow the use of much lower concentrations of both compounds to get the desired antibacterial results.
- halogenated peptides alone, the antibiotic alone or mixtures of the halogenated peptides and selected antibiotics are prepared in sterile concentrated aqueous solutions at the desired ratios. Serial dilutions are made to give a range of concentrations of the test substances. Samples of the dilutions are mixed with an appropriate sterile synthetic medium in test tubes. The tubes are then inoculated with an appropriate test organism and incubated at 35-37°C. for 16-20 hours. Minimum inhibitory concentrations, i.e., that concentration which inhibits visible growth, are read and the frac tional inhibitory concentration indices (F.I.C.) are calculated. The results obtained using representative halogenated peptides and representative antibiotics are given in Table II. In all instances, E. coli (Juhl) was used as the infecting microorganism.
- mice weighing approximately 20 g. each, are infected intraperitoneally with 10-100 times the LD of the infecting organism. At predetermined intervals post-infection, e.g., 1 and 5 hours, mice are dosed subcutaneously with graded doses of the halogenated peptide, antibiotic and combination thereof. The number of mice surviving each treatment for 7 days post-infection is observed and the CD 50 is calculated. The fractional inhibitory concentration (F.I.C.) for each combination is calculated in the usual manner. The results using D-cycloserine as an example of the antibiotic and representative halogenated peptides are shown in Table III.
- the compounds of the present invention can be administered intramuscularly, orally, subcutaneously or intravenously.
- Sterile, liquid dosage forms can easily be prepared for parenteral administration by dissolving the above dipeptide in the form of a water-soluble, non-toxic salt in isotonic sodium chloride solutions containing optional buffers, stabilizers, and/or preservatives.
- Liquid oral dosage forms in the form of elixirs, syrups or suspensions can be made in standard fashion, also optionally containing the above additives together with coloring or flavoring agents.
- Solid dosage forms for oral administration include tablets, capsules, pills and wafers.
- the usual solid diluents are used where required.
- Capsules can be filled with undiluted powdered or granulated crystals of the new compounds.
- the following standard procedure may be used:
- comstarch About one-half of 50 g. of comstarch is milled together with 50 g. of the above dipeptide and 220 g. of calcium phosphate dibasic dihydrate. This blend is milled until homogenous and passed through a 40-mesh screen. The remaining portion of the comstarch is granulated with water, heated and mixed with the above drug blend in a hot air oven at 50°C and sifted through a 16-mesh screen. These granules are then mixed with 16 g. of talcum powder, 4 g. of magnesium stearate and 0.8 g. of combined coloring and flavoring additives. The mixture is blended to homogeneity, passed through a 30-mesh screen and blended for another 15 minutes.
- This blend is compressed into tablets weighing approximately 350 mg. using a 9/32" standard convex punch resulting in tablets of a hardness of 7-9 with each tablet containing 50 mg. of the drug.
- tablets weighing 600 mg. containing 250 mg. of drug can be prepared, preferably in a tableting machine producing bisected tablets.
- the nontoxic salts useful as antibacterials include primarily the hydrochloride, phosphate, sulfate, acetate, succinate and citrate.
- the current dipeptides are antibacterially active in warmblooded animals.
- the new dipeptides are powerful synergists for known antibacterials, enabling the use of the latter in quantities of only a small fraction of its curative dose.
- a medicinally useful antibiotic in a weight ratio of 1:1 to 10:1, excellent antibacterial synergism is observed. While the demonstrated synergistic results above are based on the use of specific antibiotics, it will be understood that other antibiotics including penicillins other than the above carbenicillin, cephalosporins other than cephalothin, streptomycin, erythromycin, tetracyclin, etc. can be combined with the new peptides to obtain better results than with such antibiotics alone.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Peptides Or Proteins (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK208680A DK208680A (da) | 1978-10-23 | 1980-05-13 | Antibakterielt peptid |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US95351678A | 1978-10-23 | 1978-10-23 | |
US953516 | 1978-10-23 | ||
US4167979A | 1979-05-23 | 1979-05-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1980000789A1 true WO1980000789A1 (en) | 1980-05-01 |
Family
ID=26718400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1979/000752 WO1980000789A1 (en) | 1978-10-23 | 1979-09-17 | Antibacterial peptide |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0020481A4 (it) |
JP (1) | JPS55500821A (it) |
AR (1) | AR229015A1 (it) |
AU (1) | AU528165B2 (it) |
CA (1) | CA1137468A (it) |
DK (1) | DK208680A (it) |
ES (1) | ES8100250A1 (it) |
GR (1) | GR73145B (it) |
IL (1) | IL58487A (it) |
IT (1) | IT1125557B (it) |
NZ (1) | NZ191839A (it) |
PH (1) | PH14917A (it) |
PT (1) | PT70319A (it) |
WO (1) | WO1980000789A1 (it) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1984002905A1 (en) * | 1983-01-26 | 1984-08-02 | University Patents Inc | Antibacterial peptides |
WO2006006172A2 (en) * | 2004-07-15 | 2006-01-19 | Ramot At Tel Aviv University Ltd. | Use of anti-amyloid agents for treating and typing pathogen infections |
US7491699B2 (en) | 2002-12-09 | 2009-02-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures and methods of generating and using the same |
US7504383B2 (en) | 2003-01-07 | 2009-03-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures encapsulating a foreign material and method of manufacturing same |
US7732479B2 (en) | 2004-08-19 | 2010-06-08 | Tel Aviv University Future Technology Development L.P. | Compositions for treating amyloid associated diseases |
US7786086B2 (en) | 2004-09-08 | 2010-08-31 | Ramot At Tel-Aviv University Ltd. | Peptide nanostructures containing end-capping modified peptides and methods of generating and using the same |
US7942870B2 (en) | 2003-04-03 | 2011-05-17 | Galil Medical Ltd. | Apparatus and method for accurately delimited cryoablation |
US8372880B2 (en) | 2003-09-25 | 2013-02-12 | Tel Aviv University Future Technology Development L.P. | Compositions and methods using same for treating amyloid-associated diseases |
US8563273B2 (en) | 2002-09-06 | 2013-10-22 | Tel Aviv University Future Technology Development L.P. | Method of screening for compounds that disaggregate amyloid aggregates |
US8697634B2 (en) | 2002-01-31 | 2014-04-15 | Tel Aviv University Future Technology Development L.P. | Peptides and methods using same for diagnosis and treatment of amyloid-associated disease |
US9096645B2 (en) | 2010-11-15 | 2015-08-04 | Ramot At Tel-Aviv University Ltd. | Dipeptide analogs for treating conditions associated with amyloid fibril formation |
US9394628B2 (en) | 2004-08-02 | 2016-07-19 | Ramot At Tel-Aviv University Ltd. | Method of forming a fiber made of peptide nanostructures |
US10004828B2 (en) | 2005-10-11 | 2018-06-26 | Romat at Tel-Aviv University Ltd. | Self-assembled Fmoc-ff hydrogels |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU742278B2 (en) * | 1996-10-29 | 2001-12-20 | Graeme Smith | A stump |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3956367A (en) * | 1972-02-03 | 1976-05-11 | Merck & Co., Inc. | 3-Fluoro-D-alanine and pharmacologically acceptable esters, and pharmacologically acceptable salts thereof |
US4028405A (en) * | 1974-10-15 | 1977-06-07 | Merck & Co., Inc. | Fluorinated amino acids |
US4031231A (en) * | 1974-06-13 | 1977-06-21 | Merck & Co., Inc. | Antibacterial composition comprising 3-fluoro-D-alanine or deutero analog in combination with auto-antagonist inhibitor |
-
1975
- 1975-10-15 PH PH23169A patent/PH14917A/en unknown
-
1979
- 1979-09-17 JP JP50168679A patent/JPS55500821A/ja active Pending
- 1979-09-17 WO PCT/US1979/000752 patent/WO1980000789A1/en unknown
- 1979-10-12 NZ NZ191839A patent/NZ191839A/xx unknown
- 1979-10-16 PT PT70319A patent/PT70319A/pt unknown
- 1979-10-17 GR GR60286A patent/GR73145B/el unknown
- 1979-10-18 IL IL7958487A patent/IL58487A/xx unknown
- 1979-10-22 ES ES485269A patent/ES8100250A1/es not_active Expired
- 1979-10-22 IT IT7926703A patent/IT1125557B/it active
- 1979-10-22 CA CA000338128A patent/CA1137468A/en not_active Expired
- 1979-10-23 AR AR278595A patent/AR229015A1/es active
- 1979-10-23 AU AU52040/79A patent/AU528165B2/en not_active Expired - Fee Related
-
1980
- 1980-05-07 EP EP19790901311 patent/EP0020481A4/en not_active Withdrawn
- 1980-05-13 DK DK208680A patent/DK208680A/da not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3956367A (en) * | 1972-02-03 | 1976-05-11 | Merck & Co., Inc. | 3-Fluoro-D-alanine and pharmacologically acceptable esters, and pharmacologically acceptable salts thereof |
US4031231A (en) * | 1974-06-13 | 1977-06-21 | Merck & Co., Inc. | Antibacterial composition comprising 3-fluoro-D-alanine or deutero analog in combination with auto-antagonist inhibitor |
US4028405A (en) * | 1974-10-15 | 1977-06-07 | Merck & Co., Inc. | Fluorinated amino acids |
Non-Patent Citations (1)
Title |
---|
Journal of Medicinal Chemistry, No. 11, issued 1977 (U.S.), GOODACRE et al, "Antibacterial Halogenoacetyl Derivatives of Amino Acids and Simple Peptides". See pages 1445-1448. * |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1984002905A1 (en) * | 1983-01-26 | 1984-08-02 | University Patents Inc | Antibacterial peptides |
US8993510B2 (en) | 2002-01-31 | 2015-03-31 | Tel Aviv University Future Technology Development L.P. | Peptides and methods using same for diagnosis and treatment of amyloid-associated disease |
US8697634B2 (en) | 2002-01-31 | 2014-04-15 | Tel Aviv University Future Technology Development L.P. | Peptides and methods using same for diagnosis and treatment of amyloid-associated disease |
US8563273B2 (en) | 2002-09-06 | 2013-10-22 | Tel Aviv University Future Technology Development L.P. | Method of screening for compounds that disaggregate amyloid aggregates |
US8927689B2 (en) | 2002-12-09 | 2015-01-06 | Ramot At Tel-Aviv University Ltd. | Peptide nanostructures and methods of generating and using the same |
US7491699B2 (en) | 2002-12-09 | 2009-02-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures and methods of generating and using the same |
US7504383B2 (en) | 2003-01-07 | 2009-03-17 | Ramot At Tel Aviv University Ltd. | Peptide nanostructures encapsulating a foreign material and method of manufacturing same |
US7942870B2 (en) | 2003-04-03 | 2011-05-17 | Galil Medical Ltd. | Apparatus and method for accurately delimited cryoablation |
US8372880B2 (en) | 2003-09-25 | 2013-02-12 | Tel Aviv University Future Technology Development L.P. | Compositions and methods using same for treating amyloid-associated diseases |
WO2006006172A3 (en) * | 2004-07-15 | 2006-05-04 | Univ Ramot | Use of anti-amyloid agents for treating and typing pathogen infections |
WO2006006172A2 (en) * | 2004-07-15 | 2006-01-19 | Ramot At Tel Aviv University Ltd. | Use of anti-amyloid agents for treating and typing pathogen infections |
US9394628B2 (en) | 2004-08-02 | 2016-07-19 | Ramot At Tel-Aviv University Ltd. | Method of forming a fiber made of peptide nanostructures |
US7732479B2 (en) | 2004-08-19 | 2010-06-08 | Tel Aviv University Future Technology Development L.P. | Compositions for treating amyloid associated diseases |
US8889729B2 (en) | 2004-08-19 | 2014-11-18 | Tel Aviv University Future Technology Development L.P. | Compositions for treating amyloid associated diseases |
US7786086B2 (en) | 2004-09-08 | 2010-08-31 | Ramot At Tel-Aviv University Ltd. | Peptide nanostructures containing end-capping modified peptides and methods of generating and using the same |
US10004828B2 (en) | 2005-10-11 | 2018-06-26 | Romat at Tel-Aviv University Ltd. | Self-assembled Fmoc-ff hydrogels |
US9096645B2 (en) | 2010-11-15 | 2015-08-04 | Ramot At Tel-Aviv University Ltd. | Dipeptide analogs for treating conditions associated with amyloid fibril formation |
US9630989B2 (en) | 2010-11-15 | 2017-04-25 | Ramot At Tel-Aviv University Ltd. | Dipeptide analogs for treating conditions associated with amyloid fibril formation |
Also Published As
Publication number | Publication date |
---|---|
AR229015A1 (es) | 1983-05-31 |
IL58487A0 (en) | 1980-01-31 |
DK208680A (da) | 1980-05-13 |
AU528165B2 (en) | 1983-04-14 |
EP0020481A1 (en) | 1981-01-07 |
AU5204079A (en) | 1980-05-01 |
PH14917A (en) | 1982-01-29 |
PT70319A (en) | 1979-11-01 |
CA1137468A (en) | 1982-12-14 |
EP0020481A4 (en) | 1981-04-24 |
IT7926703A0 (it) | 1979-10-22 |
ES485269A0 (es) | 1980-11-01 |
ES8100250A1 (es) | 1980-11-01 |
GR73145B (it) | 1984-02-09 |
NZ191839A (en) | 1983-02-15 |
IT1125557B (it) | 1986-05-14 |
IL58487A (en) | 1982-09-30 |
JPS55500821A (it) | 1980-10-23 |
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