ES2509959T3 - Métodos y composiciones - Google Patents

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ES2509959T3
ES2509959T3 ES12151953.2T ES12151953T ES2509959T3 ES 2509959 T3 ES2509959 T3 ES 2509959T3 ES 12151953 T ES12151953 T ES 12151953T ES 2509959 T3 ES2509959 T3 ES 2509959T3
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exposure
polypeptide
peptides
nucleic acid
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Gregory Winter
Christian Heinis
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Bicycle Therapeutics PLC
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    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1062—Isolating an individual clone by screening libraries mRNA-Display, e.g. polypeptide and encoding template are connected covalently
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1041—Ribosome/Polysome display, e.g. SPERT, ARM
    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1068—Template (nucleic acid) mediated chemical library synthesis, e.g. chemical and enzymatical DNA-templated organic molecule synthesis, libraries prepared by non ribosomal polypeptide synthesis [NRPS], DNA/RNA-polymerase mediated polypeptide synthesis
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C40B40/08—Libraries containing RNA or DNA which encodes proteins, e.g. gene libraries
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/06—Biochemical methods, e.g. using enzymes or whole viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof

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  • Health & Medical Sciences (AREA)
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  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Analytical Chemistry (AREA)
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Abstract

Colección de polipéptidos codificados genéticamente de complejos que comprenden un ácido nucleico que codifica un polipéptido, en donde: (i) el polipéptido codificado por el ácido nucleico está unido al ácido nucleico; (ii) un compuesto conector unido a dicho polipéptido; (iii) el compuesto conector está unido al polipéptido mediante al menos tres enlaces covalentes independientes; y (iv) la colección es una genoteca exposición de ARNm, exposición de ADN, exposición en levadura, exposición en ribosomas o exposición en bacterias.

Description

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E12151953
02-10-2014
calicreína plasmática humana (<2000 Da). Nuestro mejor inhibidor (PK15) con Ki = 1,5 nM interrumpe con eficacia la vía de la coagulación intrínseca en el plasma humano analizado ex vivo, y era muy específico: no inhibía la calicreína plasmática de ratón ni las proteasas plasmáticas homólogas humanas factor XIa y trombina.
Nuestro repertorio se construyó a partir de péptidos de 17 restos con tres cisteínas, separadas entre sí por seis
5 aminoácidos aleatorios. Después de la conjugación con TBMB, se espera que los péptidos formen dos lazos de seis restos unidos a un núcleo de mesitileno, como se confirmó realmente gracias a la estructura del inhibidor de la calicreína PK15 resuelto por RMN (figura 14). Tales péptidos policíclicos deben tener ventajas tanto sobre los péptidos con puentes disulfuro como con los lineales. Las ventajas de los péptidos policíclicos sobre los péptidos con puentes disulfuro son que los enlaces covalentes azufre-carbono, una vez que se forman, son inertes para el
10 intercambio18, y también son estables en un entorno reductor18. La ventaja de los péptidos policíclicos sobre los péptidos lineales es que están interconectados y más constreñidos. Esto tiene dos consecuencias principales: (a) los péptidos constreñidos se espera que se unan más estrechamente a las dianas (debido a la menor pérdida de entropía conformacional). Nuestra revisión de la bibliografía sobre inhibidores peptídicos que se han aislado por exposición en fagos muestra que la mayoría contienen puentes disulfuro y tienen constantes de inhibición del orden
15 micromolar (tabla 3).
Tabla 3: Inhibidores peptídicos seleccionados en fagos. Se indican la secuencia de los péptidos, la diana de la enzima y la afinidad de unión. Los restos de cisteína que forman puentes disulfuro están subrayados.
Diana
Secuencia peptídica Afinidad Referencia
Antígeno prostático específico (PSA)
imagen36 KD = 2,9 µM 1
Calicreína 2 humana
imagen37 CI50 = 3,4 µM 2
Activador del plasminógeno de tipo urocinasa (uPA)
imagen38 Ki = 6,7 µM 3
Activador del plasminógeno de tipo urocinasa (uPA)
imagen39 Ki = 0,4 µM 4
Quimotripsina
imagen40 Ki = 1 µM 5
TF-fVII
imagen41 CI50 = 1,5 nM 6
Enzima convertidora de la angiotensina 2 (ACE2)
imagen42 KI = 2,8 nM 7
ErbB-2
imagen43 Ki = 30 µM 8
Ureasa
imagen44 CI50 = 30 µM 9
Lipasa pancreática
imagen45 CI50 = 16 µM 10
β-Lactamasa
imagen46 CI50 = 9 µM 11
DNasa II
imagen47 KI = 0,2 µM 12
Sólo dos inhibidores peptídicos fueron tan potentes como la PK15; ambos contenían un puente disulfuro y al menos
20 dos restos de triptófano19-20 . Esto sugiere que (a) la conformación constreñida y la posibilidad de formar interacciones hidrófobas son clave para estas afinidades elevadas; (b) los péptidos constreñidos (e interconectados) también deben ser más resistentes a la escisión y/o inactivación que los péptidos lineales. De hecho, en nuestro trabajo se escindió uno de los lazos del inhibidor PK15 después de la incubación prolongada con la calicreína plasmática humana, pero permaneció intacta y activa.
25 Los conjugados policíclicos se prestan a la ingeniería genética y química. La masa molecular del PK15 (1939,4 Da) es mayor que la de varios fármacos macrocíclicos peptídicos (tabla 2), pero sería posible utilizar lazos más pequeños. Por ejemplo, al alterar el espaciado de las cisteínas, se varía directamente la longitud del lazo, o incluso 37
E12151953
02-10-2014
se añaden segmentos adicionales a los extremos de los péptidos. Tabla 2. Comparación de tamaños de los fármacos macrocíclicos.
Nombre
Tamaño del ciclo o de los ciclos Masa molecular (Da) Aplicación
Actinomicina
16,16 1255,42 Antineoplásico
Amfotericina B
38 924,08 Antimicótico
Azitromicina
15 748,88 Antibiótico
Caspofungina
21 1093,31 Antimicótico
Ciclosporina
32 1202,61 Inmunodepresor
Daptomicina
31 1619,71 Antibiótico
Eritromicina
14 733,93 Antibiótico
Ixabepilona
16 506,70 Antineoplásico
Ocreótido
20 1019,24 Hormona
Oxitocina
20 1007,19 Hormona
Polimixina B
23 1301,56 Antibiótico
Rapamicina
29 914,17 Inmunodepresor
Rifabutina
27 847,01 Antibiótico
Vancomicina
16, 16, 12 1449,30 Antibiótico
Otras variaciones podrían incluir la mutagénesis de los lazos (como con la maduración de la afinidad de PK15); la
5 escisión proteolítica de uno o ambos lazos para generar segmentos peptídicos «ramificados» en las cisteínas; conjugación química en los extremos del péptido naciente después de la escisión de lazo21; o el uso de variaciones en los núcleos orgánicos. Por ejemplo, un núcleo orgánico más grande, o uno con más grupos funcionales podría interaccionar más extensivamente con los lazos o con la diana, y también se podrían utilizar para introducir funciones completamente nuevas, tales como la fluorescencia. Si se realizasen estas operaciones sobre el
10 conjugado expuesto en fagos, se podrían seleccionar las variaciones mediante un proceso reiterativo. Dado que los conjugados peptídicos también son adecuados para la síntesis química, se podrían introducir sintéticamente más variaciones (tales como la sustitución mediante aminoácidos no naturales).
Los inhibidores de la calicreína plasmática humana se han desarrollado clínicamente para el tratamiento del angioedema hereditario y para la intervención quirúrgica para la derivación coronaria, pero se ha demostrado que es
15 difícil fabricar moléculas pequeñas que sean específicas de la calicreína (revisado en22,23). El hecho de que nosotros obtengamos fácilmente un inhibidor muy específico y de gran afinidad mediante la selección reiterativa de conjugados peptídicos policíclicos sobre los fagos indica que esta estrategia está bien encaminada.
Materiales y métodos
Modificación química con TBMB de los repertorios peptídicos sobre los fagos
20 Las genotecas de péptidos en fagos que se basan en el plásmido fdg3p0ss2116 se clonaron y se produjeron como se describe más adelante. Típicamente, los fagos purificados con PEG a 1011-1012 u.t. se redujeron en 20 ml de NH4HCO3 a 20 mM, pH 8 con TCEP a 1 mM a 42 ºC durante 1 hora. Los fagos se centrifugaron a 4000 rpm en un filtro Vivaspin 20 (masa molecular límite de 10 000) para reducir el volumen del tampón de reducción a 1 ml y se lavó dos veces con 10 ml de tampón de reacción enfriado en hielo (NH4HCO3 a 20 mM y EDTA a 5 mM, pH 8). El
38
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Claims (1)

  1. imagen1
    imagen2
ES12151953.2T 2008-02-05 2009-02-04 Métodos y composiciones Active ES2509959T3 (es)

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GBGB0802079.4A GB0802079D0 (en) 2008-02-05 2008-02-05 Method and compositions
GB0802079 2008-02-05
GB0818399 2008-10-08
GB0818399A GB0818399D0 (en) 2008-10-08 2008-10-08 Methods and compositions

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EP (5) EP2653545A1 (es)
JP (2) JP6074574B2 (es)
AT (1) ATE555200T1 (es)
AU (1) AU2009211253B2 (es)
CA (1) CA2714477C (es)
DK (2) DK2474613T3 (es)
ES (2) ES2509959T3 (es)
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JP2013518807A (ja) * 2010-02-04 2013-05-23 メディカル リサーチ カウンシル 多重特異性ペプチド
JP2013518558A (ja) * 2010-02-04 2013-05-23 メディカル リサーチ カウンシル 構造化されたペプチドプロセシング
GB201012410D0 (en) 2010-07-23 2010-09-08 Medical Res Council Intracellular immunity
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