WO2000047725A1 - Enzymes de nitroreductase - Google Patents

Enzymes de nitroreductase Download PDF

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Publication number
WO2000047725A1
WO2000047725A1 PCT/GB2000/000431 GB0000431W WO0047725A1 WO 2000047725 A1 WO2000047725 A1 WO 2000047725A1 GB 0000431 W GB0000431 W GB 0000431W WO 0047725 A1 WO0047725 A1 WO 0047725A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitroreductase
sequence
reduces
derivative
prodrug
Prior art date
Application number
PCT/GB2000/000431
Other languages
English (en)
Inventor
Nigel Minton
Gill Anlezark
Thomas Vaughan
Original Assignee
Microbiological Research Authority
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Microbiological Research Authority filed Critical Microbiological Research Authority
Priority to AU24511/00A priority Critical patent/AU777860B2/en
Priority to EP00902770A priority patent/EP1151083A1/fr
Priority to JP2000598625A priority patent/JP2002536015A/ja
Priority to CA002362523A priority patent/CA2362523A1/fr
Publication of WO2000047725A1 publication Critical patent/WO2000047725A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
    • C12N9/0036—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on NADH or NADPH (1.6)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention is based upon the discovery, purification, gene sequencing and/or expression of nitroreductases in bacteria and other microorganisms with hitherto unknown properties in converting prodrugs such as CB1 954 into toxic derivatives. These nitroreductases posses properties which alone or in combination offer potential improvements compared with the known enzymes in this technology.
  • the nitroreductases of the invention may be divided into different families based upon such characteristics as activity, product spectrum and/or amino acid sequence, and each given nitroreductase may fall into more than one of these families.
  • the present invention provides, in a first aspect, a nitroreductase enzyme, characterised in that it preferentially reduces CB1 954 to a product that is a cytotoxic 4-hydroxylamine (4HX) derivative.
  • the present invention further provides, in a second aspect, a nitroreductase enzyme, characterised in that it reduces a prodrug to a toxic derivative with a K m of less 700 micromolar, wherein the prodrug is selected from CB1 954 and analogues thereof or other bioreductive drugs (Denny et al, BJ .
  • B. subtil is YrkL (85-90) His Gly Trp Ala Tyr Gly

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Wood Science & Technology (AREA)
  • Public Health (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des polypeptides et des protéines possédant une activité de nitroréductase. L'invention concerne aussi des ADN et des gènes codant pour ces nitroréductases ainsi que des procédés d'obtention de ces enzymes, ADN et gènes. Dans un mode de réalisation particulièrement préféré, les enzymes de nitroréductase manifestent une conversion catalytique de l'agent d'alkylation CB1954 en son dérivé hautement cytotoxique 4-hydroxylamine (4HX), ledit dérivé manifestant des propriétés anticarcinomiques; de ce fait, l'activité catalytique des enzymes de nitroréductase de la présente invention peut s'utiliser pour effectuer la conversion catalytique de CB1954 en son dérivé cytotoxique selon un procédé agissant sur le site tel que la thérapie par promédicaments à enzymes dirigées (DEPT).
PCT/GB2000/000431 1999-02-10 2000-02-10 Enzymes de nitroreductase WO2000047725A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU24511/00A AU777860B2 (en) 1999-02-10 2000-02-10 Nitroreductase enzymes
EP00902770A EP1151083A1 (fr) 1999-02-10 2000-02-10 Enzymes de nitroreductase
JP2000598625A JP2002536015A (ja) 1999-02-10 2000-02-10 ニトロレダクターゼ酵素
CA002362523A CA2362523A1 (fr) 1999-02-10 2000-02-10 Enzymes de nitroreductase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9903019.9 1999-02-10
GBGB9903019.9A GB9903019D0 (en) 1999-02-10 1999-02-10 Nitroreductase enzymes

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09913068 A-371-Of-International 2001-12-28
US10/364,397 Continuation-In-Part US20040014191A1 (en) 1999-02-10 2003-02-12 Nitroreductase enzymes

Publications (1)

Publication Number Publication Date
WO2000047725A1 true WO2000047725A1 (fr) 2000-08-17

Family

ID=10847495

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/000431 WO2000047725A1 (fr) 1999-02-10 2000-02-10 Enzymes de nitroreductase

Country Status (6)

Country Link
EP (1) EP1151083A1 (fr)
JP (1) JP2002536015A (fr)
AU (1) AU777860B2 (fr)
CA (1) CA2362523A1 (fr)
GB (1) GB9903019D0 (fr)
WO (1) WO2000047725A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011026898A3 (fr) * 2009-09-02 2011-11-10 Bangor University Système d'activation de médicament
WO2015075475A1 (fr) * 2013-11-22 2015-05-28 The University Of Nottingham Traitement contre le cancer
EP2570478A4 (fr) * 2010-05-12 2015-12-16 Amano Enzyme Inc Réducteur dérivé de micro-organisme appartenant au genre bacillus, et application de celui-ci
US10357577B2 (en) 2010-07-16 2019-07-23 Auckland Uniservices Limited Bacterial nitroreductase enzymes and methods relating thereto
EP4299736A2 (fr) 2022-04-15 2024-01-03 Vilnius University Hydrolases et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4221830A1 (de) * 1991-07-25 1993-01-28 Biotechnolog Forschung Gmbh Vektor fuer 26,8-kd nadh-gen, wirt und verwendung
EP0540263A1 (fr) * 1991-10-23 1993-05-05 Cancer Research Campaign Technology Limited Nitroréductase bactérienne pour la réduction de CB 1954 et analogues à une forme cytotoxique
EP0547876A1 (fr) * 1991-12-16 1993-06-23 Chisso Corporation Gène codant pour un enzyme avec activité réduisant les flavines et activité nitroréductase
WO1995012678A2 (fr) * 1993-11-05 1995-05-11 Cancer Research Campaign Technology Limited Ameliorations se rapportant a la therapie du cancer
WO1998057662A2 (fr) * 1997-06-14 1998-12-23 Enzacta R & D Limited Systemes therapeutiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4221830A1 (de) * 1991-07-25 1993-01-28 Biotechnolog Forschung Gmbh Vektor fuer 26,8-kd nadh-gen, wirt und verwendung
EP0540263A1 (fr) * 1991-10-23 1993-05-05 Cancer Research Campaign Technology Limited Nitroréductase bactérienne pour la réduction de CB 1954 et analogues à une forme cytotoxique
EP0547876A1 (fr) * 1991-12-16 1993-06-23 Chisso Corporation Gène codant pour un enzyme avec activité réduisant les flavines et activité nitroréductase
WO1995012678A2 (fr) * 1993-11-05 1995-05-11 Cancer Research Campaign Technology Limited Ameliorations se rapportant a la therapie du cancer
WO1998057662A2 (fr) * 1997-06-14 1998-12-23 Enzacta R & D Limited Systemes therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANTELMANN H. ET AL.: "First step from a two-dimensional protein index towards a response-regulation map for Bacillus subtilis", ELECTROPHORESIS, vol. 18, no. 8, 1997, pages 1451 - 1463, XP000923464 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011026898A3 (fr) * 2009-09-02 2011-11-10 Bangor University Système d'activation de médicament
US9089613B2 (en) 2009-09-02 2015-07-28 Bangor University Drug activation system
EP2570478A4 (fr) * 2010-05-12 2015-12-16 Amano Enzyme Inc Réducteur dérivé de micro-organisme appartenant au genre bacillus, et application de celui-ci
US9241507B2 (en) 2010-05-12 2016-01-26 Amano Enzyme Inc. Reducing agent from microorganism belonging to genus Bacillus and application for same
US10357577B2 (en) 2010-07-16 2019-07-23 Auckland Uniservices Limited Bacterial nitroreductase enzymes and methods relating thereto
WO2015075475A1 (fr) * 2013-11-22 2015-05-28 The University Of Nottingham Traitement contre le cancer
US10183062B2 (en) 2013-11-22 2019-01-22 The University Of Nottingham Treatment for cancer
EP4299736A2 (fr) 2022-04-15 2024-01-03 Vilnius University Hydrolases et leurs utilisations

Also Published As

Publication number Publication date
JP2002536015A (ja) 2002-10-29
AU777860B2 (en) 2004-11-04
CA2362523A1 (fr) 2000-08-17
GB9903019D0 (en) 1999-03-31
AU2451100A (en) 2000-08-29
EP1151083A1 (fr) 2001-11-07

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