WO2013042093A1 - Utilisation de l'antibiotique bacitracine dans la dégradation hydrolytique d'arn - Google Patents

Utilisation de l'antibiotique bacitracine dans la dégradation hydrolytique d'arn Download PDF

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Publication number
WO2013042093A1
WO2013042093A1 PCT/IB2012/055059 IB2012055059W WO2013042093A1 WO 2013042093 A1 WO2013042093 A1 WO 2013042093A1 IB 2012055059 W IB2012055059 W IB 2012055059W WO 2013042093 A1 WO2013042093 A1 WO 2013042093A1
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rna
bacitracin
degradation
dna
concentration
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PCT/IB2012/055059
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English (en)
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WO2013042093A8 (fr
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Centrum Badań Eit+ Sp. Z O.O. Wrocławskie
Jerzy CIESIOŁKA
Małgorzata JEŻOWSKA-BOJCZUK
Jan WRZESIŃSKI
Justyna NAGAJ
Kamila STOKOWA-SOŁTYS
Aleksandra KASPROWICZ
Leszek BŁASZCZYK
Wojciech SZCZEPANIK
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Wroclawskie Centrum Badan Eit Sp Z O O
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Publication of WO2013042093A1 publication Critical patent/WO2013042093A1/fr
Publication of WO2013042093A8 publication Critical patent/WO2013042093A8/fr

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    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • Bacitracin is a polypeptide complex of known antibacterial properties, produced by Bacillus subtilis var. Tracy and Bacillus licheniformis.
  • This drug is not absorbed enterically, and is most often used as a component of antibiotic ointments for counteracting skin infections as well as against bacterial eye infections. It is also administered intramuscularly, including infants with bacterial pneumoniae. Moreover, bacitracin is used as a feed additive for preventing infection in animals.
  • Bacitracin is a strongly nephrotoxic antibiotic. Bacitracin cofactors include bivalent metals, and activated bacitracin exhibits antibacterial and antifungal properties.
  • Bacitracin is a drug that has been permitted for marketing for a long time, and thus any questions relating to the side effects connected with its use, such as its nephrotoxicity or allergenicity have been thoroughly studied (Podlewski, J.K., Chwalibogowska-Podlewska A. Leki wspolczesnej terapii - XX edition, Medical Tribune Polska, Warszawa 2010).
  • US 4795740 and US 5066783 disclose a pharmaceutical composition effective against HS V, which consists of a mixture of acyclovir and bacitracin (as a protease inhibitor), wherein it was shown in the control sample that bacitracin alone does not exhibit activity against HSV-1.
  • the subject of the present invention is the use of bacitracin in the manufacture of preparations for the degradation of RNA.
  • RNA include, amongst others, hepatitis and polio viruses, as well as HIV.
  • Local use could also include use against rapidly multiplying DNA viruses, such as the herpes simplex virus, through attacking viral mRNA.
  • Antiviral therapies used to date make use of low molecular weight compounds which inhibit enzymes important for the viral life cycle such as RNA polymerase essential for the synthesis of the strands of this acid, the protease involved in the generation of the viral envelope proteins, etc. Practically none of the antibiotics used, effective against bacterial infections, is used in antiviral therapy. Quite the opposite, it is thought that these compounds are ineffective against viral infections.
  • Fig. 1 represents the model RNA and DNA used in the evaluation of the nucleolytic properties of bacitracin: tRNAPhe-RNA, phenylalanine-specific tRNA isolated from yeast; ribHDV-RNA, antigenomic ribozyme HDV; R20-RNA, 20-nucleotide HDV fragment; M39- DNA, 39-nucleotide DNA oligomer; M72-DNA, 72-nucleotide DNA oligomer. The main sites of degradation in the presence of bacitracin are shown;
  • Fig. 2 represents an autoradiogram of the degradation of tRNAPhe-RNA as a result of varying concentrations of bacitracin (Bac), its complex with Cu(II) ions, as well as complexes in the presence of H 2 0 2 (concentrations in uM).
  • Reaction conditions 50 mM Tris-HCl buffer pH 7.5; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml.
  • Fig. 3 represents the effect of the concentration of bacitracin, its complex with Cu(II) ions as well as the complex in the presence of H 2 0 2 on the degree of degradation tRNAPhe-RNA;
  • Fig. 4 represents an autoradiogram showing the degradation of ribHDV-RNA as an effect of varying concentrations of bacitracin (Bac) as well as its complex with Cu(II) ions (concentrations in ⁇ ), under the following reaction conditions: 50 mM Tris-HCl buffer pH 7.5; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml. Kl-control lane; K2- 50 uM Cu(II); L-alkaline hydrolysis; T-digestion with ribonuclease Tl;
  • Fig. 5 represents the effect of the concentration of bacitracin as well as its complex with Cu(II) ions on the degree of degradation ribHDV-RNA;
  • Fig. 6 represents an autoradiogram showing the degradation of R20-RNA as an effect of varying concentrations of bacitracin (Bac) as well as its complex with Cu(II) ions (concentrations in ⁇ ), under the following reaction conditions: 50 mM Tris-HCl buffer pH 7.5; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml. Kl-control lane; K2- 50 uM Cu(II); L-alkaline hydrolysis; T-digestion with ribonuclease Tl;
  • Fig. 7 represents the effect of the concentration of bacitracin as well as its complex with Cu(II) ions on the degree of degradation R20-RNA;
  • Fig. 8 represents an autoradiogram showing the degradation of tRNAPhe-RNA in the presence of bacitracin (Bac) as well as its complex with Cu(II) ions at a concentration of 22 ⁇ depending on time (in minutes), under the following reaction conditions: 50 mM Tris-HCl buffer pH 7.5; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml. K-control lane; L-alkaline hydrolysis; T-digestion with ribonuclease Tl;
  • Fig. 9 represents the progress of the degradation tRNAPhe-RNA in the presence of bacitracin as well as its complex with Cu(II) ions at a concentration of 22 ⁇ depending on the time of incubation
  • Fig. 10 represents an autoradiogram showing the degradation of R20-RNA in the presence of bacitracin (Bac) as well as its complex with Cu(II) ions (Bac-Cu) at a concentration of 22 ⁇ depending on time (in minutes), under the following reaction conditions: 50 mM Tris-HCl buffer pH 7.5; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml. K-control lane; L-alkaline hydrolysis; T-digestion with ribonuclease Tl;
  • Fig. 11 represents the progress of the degradation R20-RNA in the presence of bacitracin as well as its complex with Cu(II) ions at a concentration of 22 ⁇ depending on time of incubation;
  • Fig. 12 represents an autoradiogram showing the degradation of ribHDV-RNA as an effect bacitracin activity at a concentration of 5 and 25 uM in the presence of selected factors potentially affecting the degradation reaction, under the following reaction conditions: 50 mM HEPES-NaOH buffer pH 7.0; temp. 37°C; time 60 minutes; total concentration of RNA 2 OD/ml, K- control lanes;
  • Fig. 13 represents the progress of the degradation of ribHDV-RNA as a result of bacitracin at a concentration of 5 and 25 ⁇ in the presence of selected factors affecting the degradation;
  • Fig. 14 represents an autoradiogram showing the degradation of M39-DNA as an effect of varying concentrations of bacitracin (2.5, 25, 250 and 2500 uM) in the presence of selected factors affecting the degradation, under the following reaction conditions: temp. 37°C; time 60 minutes; total concentration of DNA 0.7 OD/ml. K- control lanes;
  • Fig. 15 represents an autoradiogram showing the degradation of M39-DNA as an effect of varying concentrations of bacitracin (Bac) (concentrations in ⁇ ) in the presence of selected factors affecting the degradation, under the following reaction conditions: temp. 37°C; time 60 minutes; total concentration of DNA 0.7 OD/ml, K-control lanes;
  • Fig. 16 represents an autoradiogram representing the degradation of M72-DNA as an effect of varying concentrations of bacitracin (25, 250 and 2500 uM) in the presence of selected factors affecting the degradation, under the following reaction conditions: 50 mM HEPES-NaOH buffer pH 7.0; temp. 37°C; time: 60 minutes; total concentration of DNA 0.2 OD/ml. K- control lane; G+A, C+A-sequence lanes;
  • Fig. 17 represents an autoradiogram showing the degradation of an R20-RNA molecule incubated in the presence of bacitracin in 50 mM HEPES-NaOH buffer pH 7.0, at a temperature of 37°C for 2 minutes, Panel Bac: 25 and 50 ⁇ bacitracin, RNA concentration 8 g/ml, Panel tRNA carrier: 25 uM bacitracin, RNA concentration 8, 0.8, 0.08 and 0.01 g/ml (-). K-control lane; L-alkaline hydrolysis; SI, Tl-digestion with nuclease SI and ribonuclease Tl ;
  • Fig. 18 shows an autoradiogram showing the degradation products of M39-DNA as an effect of varying concentrations of bacitracin (250 and 2500 ⁇ ), under the following reaction conditions: 50 mM HEPES-NaOH buffer pH 7.0; temp. 37°C; time 60 minutes; total concentration of DNA 0.2 OD/ml. K-control lane; SI -digestion with nuclease SI, C+A- sequence lane; showing the results of a short and long electrophoresis run;
  • Fig. 19 represents an autoradiogram showing the R20-RNA degradation products as an effect of varying concentrations of bacitracin (concentrations in ⁇ ), under the following reaction conditions: RNA concentration 0.01 ⁇ , 50 mM HEPES-NaOH buffer pH 7.0; temp. 37°C; time 2 minutes, K-control lane; L-alkaline hydrolysis; SI, Tl-digestion with nuclease SI and ribonuclease Tl.
  • tRNA specific for phenylalanine isolated from yeast 76 nucleotide long tRNAPhe-RNA
  • two HDV RNA fragments tRNAPhe-RNA
  • ribHDV-RNA antigenomic ribozyme HDV 72 nucleotides long
  • R20- RNA 20-nucleotide virus fragment
  • the model DNA molecules used were: a 39-nucleotide oligomer DNA (M39-DNA) as well as a 72-nucleotide oligomer DNA (M72-DNA) (Fig. 1).
  • RNA and DNA molecules were tagged with a 32 P isotope at the 5' end using T4 polynucleotide kinase and [ ⁇ - P]ATP according to a standard procedure, bacitracin reaction products were separated electrophoretically in high-resolution polyacrylamide gels, and visualised using imaging screens and a computerised radioactivity scanner: FLA-5100 (Fujifilm), and a quantitative analysis using the Multi Gauge program.
  • ribHDV-RNA The degradation of ribHDV-RNA was much more effective than of tRNAPhe-RNA (Fig. 4, 5). In the presence of 5 uM bacitracin 60% of the initial RNA was degraded. At 10 ⁇ bacitracin, the degree of degradation reached 80%, and an almost complete degradation of ribHDV-RNA was observed at 50 uM bacitracin. The 20-nucleotide oligomer R20-RNA following 60 minutes of incubation in the presence of 20 uM bacitracin underwent almost complete degradation to shorter products (Fig. 6, 7).
  • P nucleoside triphosphates [ ⁇ - P]ATP as well as [a- P]UTP, which were incubated with 25 and 250 ⁇ bacitracin for 60 minutes at a temperature of 37°C, including in the presence of Mg(II) and Mn(II) ions and EDTA, were used. No degradation products of any of these compounds following polyacrylamide gel electrophoresis have been observed.
  • bacitracin possesses a the ability to degrade single stranded DNA to some degree.
  • the degradation of M39-DNA (Fig. 14) and M72-DNA (Fig. 16) required much higher antibiotic concentrations than for RNA.
  • a comparable effect was achieved using an at least 10-fold concentration of bacitracin.
  • M39-DNA and M72-DNA degradation was observed using 250 uM bacitracin, but not at 25 ⁇ antibiotic concentration.
  • RNA alkaline hydrolysis products as well as ribonuclease Tl digestion products possess a phosphate group at the 3' end of the RNA chain, whereas nuclease SI digestion products possess it at the 5' terminus.
  • the migration of RNA fragments following degradation with bacitracin is identical with the migration of RNA fragments following alkaline hydrolysis as well as RNase Tl digestion, and different than following digestion with the SI nuclease. This is convincing evidence that phosphate groups are found at the 3' end of the arising fragments.
  • RNA degradation reaction has been conducted. It has been determined that bacitracin degrades RNA beside guanosine residues (Fig. 2,4,6).
  • the degradation occurs in single-stranded RNA regions, for tRNAPhe-RNA primarily in the D loop (G15, G18, G19) and at T C (G57), for ribHDV-RNA in the looped regions L3/P3 (G28, G30, G31) and L4 (G58), and in the single stranded R20-RNA at the G12, G13, G14, G17 and G18 residues (Fig. 2,4,6). It is interesting that a similar specific degradation of RNA is exhibited by the Tl ribonuclease.
  • RNA molecules Furthermore, it has been observed the removal by bacitracin of the phosphate group from the 5' end (or from the 5'-terminal nucleotide) of RNA molecules. This effect was observed both for tRNAPhe-RNA as well as ribHDV-RNA (Fig. 2, 4). We did not observe it in the case of R20-RNA (Fig. 6). This may stem from the fact that in the first two model RNAs, the 5'-terminal nucleoside is guanosine, in the third it is cytidine.
  • RNA degradation reaction to evaluate the dependence of this process on the RNA concentration has been conducted.
  • the observed degradation level of RNA was dependent on its total concentration.
  • the degradation effectiveness of three different RNA molecules, used at concentrations of 2 OD/ml, i.e. 80 ⁇ g/ml, incubated with 20 ⁇ bacitracin for 60 minutes at a temperature of 37°C was 80-95% of the initial amount of RNA. Decreasing the concentration of R20-RNA to 8, 0.8, 0.08 and about 0.01 ⁇ g/ml, using 25 uM bacitracin and a 2 minute incubation led to an increased degradation effect (Fig. 17).
  • the bacitracin reactions were performed in two different buffers, 50 mM Tris-HCl pH 7.5 and 50 mM HEPES-NaOH pH 7.0, without any observed significant differences in the RNA and DNA reactions.
  • ribF£DV-RNA degradation reaction in the presence of 5 and 25 ⁇ bacitracin was performed with the addition of protein ribonuclease inhibitor, RNasin (Promega), without noting any significant differences in the effectiveness of the antibiotic (Fig. 12,13).
  • the amount of undegraded RNA increased to about 70 to 80%.

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Abstract

La présente invention concerne l'utilisation de bacitracine pour la dégradation hydrolytique d'ARN, survenant au niveau de résidus guanosine, de préférence dans des régions d'ARN monocaténaire, et survenant sans l'implication d'ions de métaux de transition. Selon l'invention, il est possible d'utiliser la bacitracine selon un mécanisme dépendant de la dégradation d'ARN indésirable, différent de celui stipulé à ce jour.
PCT/IB2012/055059 2011-09-23 2012-09-23 Utilisation de l'antibiotique bacitracine dans la dégradation hydrolytique d'arn WO2013042093A1 (fr)

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PLP.396418 2011-09-23
PL396418A PL227562B1 (pl) 2011-09-23 2011-09-23 Zastosowanie antybiotyku bacytracyny do hydrolitycznej degradacji RNA

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111420024A (zh) * 2020-04-07 2020-07-17 中国科学院深圳先进技术研究院 杆菌酞a在制备预防和治疗冠状病毒的药物中的应用

Citations (3)

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Publication number Priority date Publication date Assignee Title
US4795740A (en) 1986-05-20 1989-01-03 Cohen Eric A Antiviral peptides and means for treating herpes infections
US5066783A (en) 1986-05-20 1991-11-19 Cohen Eric A Antiviral peptides and means for treating herpes infections
WO1994004185A2 (fr) 1992-08-19 1994-03-03 Trustees Of Boston University Procede pour inhiber la reduction de ponts disulfure

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US4795740A (en) 1986-05-20 1989-01-03 Cohen Eric A Antiviral peptides and means for treating herpes infections
US5066783A (en) 1986-05-20 1991-11-19 Cohen Eric A Antiviral peptides and means for treating herpes infections
WO1994004185A2 (fr) 1992-08-19 1994-03-03 Trustees Of Boston University Procede pour inhiber la reduction de ponts disulfure

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111420024A (zh) * 2020-04-07 2020-07-17 中国科学院深圳先进技术研究院 杆菌酞a在制备预防和治疗冠状病毒的药物中的应用
WO2021203704A1 (fr) * 2020-04-07 2021-10-14 中国科学院深圳先进技术研究院 Utilisation de bacitracine a dans la préparation de médicaments pour la prévention et le traitement de coronavirus
CN111420024B (zh) * 2020-04-07 2023-10-03 中国科学院深圳先进技术研究院 杆菌酞a在制备预防和治疗冠状病毒的药物中的应用

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PL227562B1 (pl) 2017-12-29
PL396418A1 (pl) 2012-02-27

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