ES2654613T3 - Promotores para una expresión aumentada de proteínas en meningococos - Google Patents
Promotores para una expresión aumentada de proteínas en meningococos Download PDFInfo
- Publication number
- ES2654613T3 ES2654613T3 ES13703562.2T ES13703562T ES2654613T3 ES 2654613 T3 ES2654613 T3 ES 2654613T3 ES 13703562 T ES13703562 T ES 13703562T ES 2654613 T3 ES2654613 T3 ES 2654613T3
- Authority
- ES
- Spain
- Prior art keywords
- promoters
- seq
- meningococci
- protein expression
- region
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
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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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
-
- 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
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
-
- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/60—Vectors containing traps for, e.g. exons, promoters
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Un ácido nucleico que comprende un promotor que tiene la SEQ ID NO: 32, la SEQ ID NO: 33 o la SEQ ID NO: 34.
Description
5
10
15
20
25
30
35
40
45
unidades arbitrarias.
La Figura 4 muestra los niveles de fHbp en vesículas aisladas de cepas con inactivación de (i) ΔpxL1ΔsynX y (ii) ΔlpxL1ΔsynXΔmltA. La Figura 4A muestra el rendimiento en mg/DO y la Figura 4B es una transferencia Western de vesículas de 0,5 µg.
La Figura 5 muestra la expresión de fHbp en dos cepas que sobreexpresan fHbp ya sea variante 1 o variante 2 en loci distintos (calles C y D) o una cepa que sobreexpresa tanto variante 1 como variante 2 en loci respectivos (calle e). La calle A es la cepa de tipo silvestre y la calle B es una inactivación de ΔfHbp de esa cepa.
La Figura 6 muestra una EGPA-DSS teñido con plata de vesículas purificadas a partir de la triple inactivación.
Las secuencias corriente arriba del sitio de inicio de la transcripción de dos variantes de fase del promotor porA meningocócico de tipo silvestre, que contienen 11 y 13 G consecutivas en la región espaciadora, son como se indica a continuación, con las regiones -35 y -10 subrayadas:
AAAAATGGTTTTTTGCGGGGGGGGGGGTATAATTGAAGAC (SEQ ID NO: 31) AAAAATGGTTTTTTGCGGGGGGGGGGGGGTATAATTGAAGAC (SEQ ID NO: 40)
La secuencia intermedia entre la regiones -35 y -10 incluye una secuencia de G11poli-G que está conectado a la variación de fase de la expresión de PorA. Para estabilizar la expresión de este promotor, se sometieron a ensayo tres modificaciones (modificaciones en minúsculas):
AAAAATGGTTTTTTGCGaGGGaGGtGGTATAATTGAAGAC ("ST1"; SEQ ID NO: 32) AAAAATtGacaTTTGCGaGGGaGGtGGTATAATTGAAGAC ("ST2"; SEQ ID NO: 33) AAAAtTGacaTTTTGCGaGGGaGGtGGTATAATTGAAGAC ("ST3"; SEQ ID NO: 34)
De este modo, en "ST1" la secuencia de G11 se interrumpió en tres lugares, dejando no más de 3 restos de G consecutivos. En "ST2" se usó la misma secuencia intermedia, pero la región -35 y se sustituyó por una región -35 de consenso TTGACA. En "ST3" se insertó un resto T adicional inmediatamente corriente abajo de la región -35.
Estos tres promotores se usaron para impulsar la expresión de una secuencia de fHbp (fHbp variante 2) en la cepa NZ98/258. Los tres promotores modificados dieron como resultado una sobreexpresión de alto nivel de fHbp en la cepa en comparación con una cepa sobreexpresadora equivalente que se ha notificado en la bibliografía [103, 104]. La mejor expresión se observó con ST2 (Figuras 1 y 2).
En experimentos adicionales el promotor de ARNr 16S se fusionó al UTR 5' del gen porA:
ATATCTTGACAGGCGGAAGGAATACTTTATAATTCGCAAC... (SEQ ID NO: 35)
Este promotor se sometió a mutación y se secuenciaron tres variantes corriente abajo de la región -35 como se indica a continuación:
ATATCTTGACAGGCGGAAGGAATACTTTATAATTCGCAAC ("wt"; SEQ ID NO: 35) ATATCTTGACAGGCGGAAGGAATACTTTATATTCGCAAC... ("n.º 5"; SEQ ID NO: 36) ATATCTTGACAGGCGGAAGGAATACTTTTAATTCGCAC... ("n.º 6"; SEQ ID NO: 37) ATATCTTGACAGGCGGAAGGAAACTTTATAATTCGCAAC... ("n.º 8"; SEQ ID NO: 38)
De este modo, en las variantes n.º 5 y n.º 6 la secuencia -10 es un pentámero y la variante n.º 6 además perdió un nucleótido entre la región -10 y el sitio de inicio de la transcripción. En la variante n.º 8 la región -10 y su secuencia corriente abajo son iguales que en wt, pero la secuencia intermedia entre las regiones -35 y -10 es un nucleótido más corta que en wt.
Estos promotores se fusionan con la región 5'UTR del gen porA y se usan para impulsar la expresión de la secuencia codificante de fHbp. Como se observa en la Figura 2, las variantes n.º 5 y n.º 6 mostraron la expresión más fuerte, acercándose a los niveles observados con ST2.
La región completa que abarca el promotor de tipo silvestre (SEQ ID NO: 35), que se extiende corriente abajo en la región transcrita y también corriente arriba, era como se indica a continuación (SEQ ID NO: 41; de 358 monómeros), con las regiones -35 y -10 subrayadas y el nucleótido +1 (siguiente referencia 10) doblemente subrayado:
14
Claims (1)
-
imagen1
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261594159P | 2012-02-02 | 2012-02-02 | |
US201261594159P | 2012-02-02 | ||
PCT/EP2013/052108 WO2013113917A1 (en) | 2012-02-02 | 2013-02-01 | Promoters for increased protein expression in meningococcus |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2654613T3 true ES2654613T3 (es) | 2018-02-14 |
Family
ID=47683718
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES13703562.2T Active ES2654613T3 (es) | 2012-02-02 | 2013-02-01 | Promotores para una expresión aumentada de proteínas en meningococos |
Country Status (11)
Country | Link |
---|---|
US (1) | US9657297B2 (es) |
EP (2) | EP2809785B1 (es) |
JP (2) | JP5957541B2 (es) |
CN (1) | CN104114706A (es) |
AU (1) | AU2013214105A1 (es) |
BR (1) | BR112014019166A2 (es) |
CA (1) | CA2861946A1 (es) |
ES (1) | ES2654613T3 (es) |
MX (1) | MX2014008988A (es) |
RU (1) | RU2014135522A (es) |
WO (1) | WO2013113917A1 (es) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG11201606478YA (en) | 2014-02-28 | 2016-09-29 | Glaxosmithkline Biolog Sa | Modified meningococcal fhbp polypeptides |
EP3607967A1 (en) | 2018-08-09 | 2020-02-12 | GlaxoSmithKline Biologicals S.A. | Modified meningococcal fhbp polypeptides |
CN109485704B (zh) * | 2018-11-27 | 2022-04-19 | 温州大学 | 一种脑膜炎球菌fHbp蛋白的表达系统 |
CN111321141B (zh) * | 2018-12-14 | 2021-02-26 | 上海凯赛生物技术股份有限公司 | 稳定期特异性启动子及其应用 |
CN111850003A (zh) * | 2020-07-09 | 2020-10-30 | 华中农业大学 | 一种重组表达的多杀性巴氏杆菌硫胺素周质结合蛋白及应用 |
CN114854701B (zh) * | 2022-03-16 | 2023-09-22 | 福建福大百特生物科技有限公司 | 一种微泡菌超氧化物歧化酶及其编码基因 |
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-
2013
- 2013-02-01 BR BR112014019166A patent/BR112014019166A2/pt not_active IP Right Cessation
- 2013-02-01 US US14/375,222 patent/US9657297B2/en active Active
- 2013-02-01 RU RU2014135522A patent/RU2014135522A/ru not_active Application Discontinuation
- 2013-02-01 AU AU2013214105A patent/AU2013214105A1/en not_active Abandoned
- 2013-02-01 JP JP2014555238A patent/JP5957541B2/ja not_active Expired - Fee Related
- 2013-02-01 CA CA2861946A patent/CA2861946A1/en not_active Abandoned
- 2013-02-01 WO PCT/EP2013/052108 patent/WO2013113917A1/en active Application Filing
- 2013-02-01 CN CN201380007752.4A patent/CN104114706A/zh active Pending
- 2013-02-01 EP EP13703562.2A patent/EP2809785B1/en active Active
- 2013-02-01 EP EP17199436.1A patent/EP3299467B1/en active Active
- 2013-02-01 ES ES13703562.2T patent/ES2654613T3/es active Active
- 2013-02-01 MX MX2014008988A patent/MX2014008988A/es unknown
-
2016
- 2016-02-22 JP JP2016030838A patent/JP2016093202A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2016093202A (ja) | 2016-05-26 |
MX2014008988A (es) | 2014-08-27 |
CN104114706A (zh) | 2014-10-22 |
JP2015506693A (ja) | 2015-03-05 |
RU2014135522A (ru) | 2016-03-27 |
US20150218566A1 (en) | 2015-08-06 |
EP3299467B1 (en) | 2021-08-11 |
EP3299467A3 (en) | 2018-05-30 |
WO2013113917A1 (en) | 2013-08-08 |
AU2013214105A1 (en) | 2014-07-24 |
JP5957541B2 (ja) | 2016-07-27 |
EP2809785A1 (en) | 2014-12-10 |
CA2861946A1 (en) | 2013-08-08 |
US9657297B2 (en) | 2017-05-23 |
EP3299467A2 (en) | 2018-03-28 |
EP2809785B1 (en) | 2017-11-01 |
BR112014019166A2 (pt) | 2017-07-04 |
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