ES2514615T3 - Proteínas de dominio Kunitz inhibidores de calicreína y ácidos nucleicos que codifican las mismas - Google Patents

Proteínas de dominio Kunitz inhibidores de calicreína y ácidos nucleicos que codifican las mismas Download PDF

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ES2514615T3
ES2514615T3 ES10164197.5T ES10164197T ES2514615T3 ES 2514615 T3 ES2514615 T3 ES 2514615T3 ES 10164197 T ES10164197 T ES 10164197T ES 2514615 T3 ES2514615 T3 ES 2514615T3
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ala
gly
ser
asn
gln
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William Markland
Robert Charles Ladner
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Dyax Corp
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Dyax Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8114—Kunitz type inhibitors
    • C07K14/8117—Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8114—Kunitz type inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/81—Protease inhibitors
    • G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • G01N2333/811—Serine protease (E.C. 3.4.21) inhibitors
    • G01N2333/8114—Kunitz type inhibitors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96455—Kallikrein (3.4.21.34; 3.4.21.35)

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  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Un polipéptido que inhibe la calicreína que comprende una estructura de dominio Kunitz que comprende la secuencia de aminoácidos: en donde: Xaa1, Xaa2, Xaa3, Xaa4, Xaa56, Xaa57 o Xaa58 pueden estar ausentes; Xaa10 se selecciona a partir de Asp, Glu, Ala, Gly, Ser, y Thr; Xaa11 se selecciona a partir de Asp, Gly, Ser, Val, Glu, Leu, Met, Asn ,Ile, Ala y Thr; Xaa13 se selecciona a partir de Arg, His, Pro, Asn, Ser, Thr, Ala, 20 Gly, Lys y Gln; Xaa15 se selecciona a partir de Arg, Lys, Ala, Ser, Gly, Met, Asn y Gln; Xaa16 se selecciona a partir de Ala, Gly, Ser, Asp, y Asn; Xaa17 se selecciona a partir de Ala, Asn, Ser, Ile, Gly, Val, Gln y Thr; Xaa18 se selecciona a partir de His, Leu, Gln, y Ala; Xaa19 se selecciona a partir de Pro, Gln, Leu, Asn, y Ile; Xaa20 se selecciona a partir de Arg, Leu, Ala, Ser, Lys, Gln, y Val; Xaa21 se selecciona a partir de Trp, Phe, Tyr, His y Ile; Xaa22 se selecciona a partir de Tyr y Phe; Xaa23 se selecciona a partir de Tyr y Phe; Xaa31 se selecciona a partir de Glu, Asp, Gln, Asn, Ser, Ala, Val, Leu, Ile y Thr; Xaa32 se selecciona a partir de Glu, Gln, Asp, Asn, Pro, Thr, Leu, Ser, Ala, Gly y Val; Xaa33 se selecciona a partir de Phe y Tyr; Xaa34 se selecciona a partir de Thr, Ile, Ser, Val, Ala, Asn, Gly y Leu; Xaa35 se selecciona a partir de Tyr, Trp y Phe; Xaa36 se selecciona a partir de Gly, Ser y Ala; Xaa39 se selecciona a partir de Gly, Glu, Ala, Ser y Asp; Xaa40 se selecciona a partir de Gly y Ala; Xaa43 se selecciona a partir de Asn y Gly; y Xaa45 se selecciona a partir de Phe y Tyr; para su uso en el tratamiento o prevención del edema de la piel, tejido subcutáneo, la laringe, el tracto respiratorio superior o el tracto gastrointestinal en un paciente, en donde dicho edema se asocia con excesiva actividad de calicreína.

Description

imagen1
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imagen5
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imagen7
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imagen9
imagen10
imagen11
imagen12
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imagen15
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Tabla 2: Secuencias de dominios Kunitz, algunos de los cuales inhiben la pKA humana.
imagen16
Secuencia de aminoácidos imagen17
imagen18
1111111111222222222233333333334444444444555555555 imagen19
Identificación
1234567890123456789012345678901234567890123456789012345678 sec. con núm. de ident..
BPTI
RPDFCLEPPYTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKRNNFKSAEDCMRTCGGA sec. con núm. de ident. 2
LACI-K1
mhsfcafkaddgpckaimkrfffniftrqceefiyggcegnqnrfesleeckkmctrd sec. con núm. de ident. 3
KBPconl
mhsfcafkaddgHckaNHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 4
KKII/3#1
mhsfcafkaddgHckASLPrfffniftrqcEEfIyggcEgnqnrfesleeckkmctrd sec. con núm. de ident. 5
KKII/3#2
mhsfcafkaddgPckANHLrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 6
KKII/3#3
mhsfcafkaddgHckANHQrfffniftrqcEEfTyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 7
KKII/3#4
mhsfcafkaddgHckANHQrfffniftrqcEQfTyggcAgnqnrfesleeckkmctrd sec. con núm. de ident. 8
KKII/3#5
mhsfcafkaddgHckASLPrfffniftrqcEEfIyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 9
KKII/3#6
mhsfcafkaddgHckANHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident.10
KKII/3#7
mhsfcafkaddgHckANHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 11
KKII/3#8
mhsfcafkaddgHckANHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 12
KKII/3#9
mhsfcafkaddgHckANHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 13
KKII/3#10
mhsfcafkaddgHckGAHLrfffniftrqcEEfIyggcEgnqnrfesleeckkmctrd sec. con núm. de ident. 14
KKI/3(a)
mhsfcafkaddgRckGAHLrfffniftrqceefiyggcegnqnrfesleeckkmctrd sec. con núm. de ident. 15
KKI/3(b)
mhsfcafkaddgPckAIHLrfffniftrqceefiyggcegnqnrfesleeckkmctrd sec. con núm. de ident. 16
KKII/3#C
mhsfcafkaddgHckANHQrfffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 17
KK2/#13
mhsfcafkaDGgRcRGAHPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 19
KK2/#14
mhsfcafkaDGgRcRGAHPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 20
KK2/#5
mhsfcafkaDDgPcRAAHPrWffniftrqcEEfSyggcGgnqnrfesleecklanctrd sec. con núm. de ident. 21
KK2/#11
mhsfcafkaDDgPcRAAHPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 22
KK2/#1
mhsfcafkaDVgRcRGAHPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 23
KK2/#4
mhsfcafkaDVgRcRGAQPrFffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 24
KK2/#6
mhsfcafkaDDgScRAAHLrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 25
17
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KK/#10
mhsfcafkaEGgScRAAHQrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 26
KK2/#8
mhsfcafkaDDgPcRGAHLrFffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 27
KK2/#3
mhsfcafkaDDgHcRGALPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 28
KK2/#9
mhsfcafkaDSgNcRGNLPrFffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 29
KKV#7
mhsfcafkaDSgRcRGNHQrFffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 30
K2/#12
mhsfcafkaDGgRcRAIQPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 31
KK2con1
mhsfcafkaDDgRcRGAHPrWffniftrqcEEfSyggcGgnqnrfesleeckkmctrd sec. con núm. de ident. 32
LACI-K2 Humano
KPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG sec. con núm. de ident. 33
DKI-1.2.1
kpdfcfleedGgRcrgAHPrWfynnqtkqceEfSyggcGgnmnnfetleecknicedg sec. con núm. de ident. 34
LACI-K3 Humano
GPSWCLTPADRGLCRANENRFYYNSVIGKCRPFKYSGCGGNENNFTSKQECLRACKKG sec. con núm. de ident. 35
DKI-1.3.1
gpswcltpadDgPcraAHPrfyynsvigkcEpfSysgcggnennftskqeclrackkg sec. con núm. de ident. 36
Colágeno Humano KuDom α3
ETDICKLPKDEGTCRDFILKWYYDPNTKSCARFWYGGCGGNENKFGSQKECEKVCAPV sec. con núm. de ident. 37
DKI-2.1
etdicklpkdegtcrAAHlkwyydpntkscaEfSyggcggnenkfgsqkecekvcapv sec. con núm. de ident. 38
TFPI-2 DOMINIO 1
NAEICLLPLDYGPCRALLLRYYYDRYTQSCRQFLYGGCEGNANNFYTWEACDDACWRI sec. con núm. de ident. 39
DKI-3.1.1
naeicllpldGgpcraAHlryyydrytqscEqfSyggcegnannfytweacddacwri sec. con núm. de ident. 40
tfpi-2 DOMINIO 2
imagen20 sec. con núm. de ident. 41
DKI-3.2.1
vpkvcrlqvs-vddqcRAAHPkyffnlssmtceEffsggchrnr-ienrfpdeatcmgfcapk sec. con núm. de ident. 42
TFPI-2 DOMINIO 3
IPSFCYSPKDEGLCSANVTRYYFNPRYRTCDAFTYTGCGGNDNNFVSREDCKRACAKA sec. con núm. de ident. 43
DKI-3.3.1
ipsfcyspkdegHcRaAHQryyfnpryrtcdaftytgcggndnnfvsredckracaka sec. con núm. de ident. 44
ITI-K1 HUMANO
KEDSCQLGYSAGPCMGMTSRYFYNGTSMACETFQYGGCMGNGNNFVTEKECLQTCRTV sec. con núm. de ident. 45
DKI-4.1.1
kedscqlgyDagpcRgAHPryfyngtsmacetfSyggcGgngnnfvtekeclqtcrtv sec. con núm. de ident. 46
ITI-K2 HUMANO
TVAACNLPIVRGPCRAFIQLWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVP sec. con núm. de ident. 47
DKI-4.2.1
tvaacnlpiDDgpcraAHqlwafdavkgkcEEfSyggcEgngnkfysekecreycgvp sec. con núm. de ident. 48
DKI-4.2.2
tvaacnlpiDDgpcraAHqRwafdavkgkcEEfSyggcqgngnkfysekecreycgvp sec. con núm. de ident. 49
PROTEASA HUMANA: NEXINA-II
VREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSA sec. con núm. de ident. 50
DKI-5.1
vrevcseqaetgpcraAHPrwyfdvtegkcEEfSyggcggnrnnfdteeycmavcgsa sec. con núm. de ident. 51
Dominio HKI B9
LPNVCAFPMEKGPCQTYMTRWFFNFETGECELFAYGGCGGNSNNFLRKEKCEKFCKFT sec. con núm. de ident. 53
DKI-6.1
lpnvcafpmeDgpcRAAHPrwffnfetgeceEfayggcggnsnnflrkekcekfckft sec. con núm. de ident. 54
DKI-7.1
rpdfcleppEtgpcRaAHPryfynakaglcEEfvyggcGakrnnfksaedcmrtcgga sec. con núm. de ident. 55
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La Tabla 3 está anteriormente. TABLA 8: Datos de Unión para la exposición de fagos seleccionada que se une a Calicreína.
5
10
15
20
25
30
35
40
45
50
55
Fagos de exposición(a)
Fracción Unida (b) Unión Relativa (c)
LACI
4 x 10 -6 1.0
BPTI
2 x 10 -5 6.0
KKI/3(a)
3,649 x 10 -3 761
KKI/3(b)
2 x 10 -3 524
KKII/3#5
3,649 x 10 -3 928
KKII/3#6
8 x 10 -3 2071
(a) Aislamientos clonales de fagos de exposición. LACI-K1 es la molécula parental, BPTI (inhibidor de la tripsina pancreática bovina) es un control y KKII/3 (5 y 6) y KKI/3(a y b) fueron seleccionados por su unión a la proteasa diana, calicreína. (b) El número de ufp eluidas después de un experimento de unión como una fracción del número de entrada (1010 ufp). (c) Fracción unida relativa al fagos de exposición parental, LACI-K1.
Tabla 9: Sustituciones Conservativas y Semiconservativas
Tipo AA inicial
Categoría Sustitución conservativa Sustitución semi-conservativa
a
Pequeño no polar o ligeramente polar G, S, T N, V, P, (C)
C
SH libre A, M, L, V, I F, G
disulfuro
nada nada
D
acídico, hidrofílico E, N, S, T, Q K, R, H, A
E
acídico, hidrofílico D, Q, S, T, N K, R, H, A
F
aromático W, Y, H, L, M I, V, (C)
G
conformación de solo Gly nada nada
conformación "normal"
A, S, N, T D, E, H, I, K, L, M, Q, R, V
H
anfotérico aromático Y, F, K, R L, M, A, (C)
I
alifático, ramificado carbono β V, L, M, A F, Y, W, G (C)
K
básico R, H Q, N, S, T, D, E, A
L
alifático M, I, V, A F, Y, W, H, (C)
M
hidrofóbico L, I, V, A Q, F, Y, W, (C), (R), (K), (E)
N
no-polar hidrofílico S, T, (D), Q, A, G, (E) K, R
P
inflexible V, I A, (C), (D), (E), F, H, (K), L, M, N, Q, (R), S, T, W, Y
Q
alifático más amida N, E, A, S, T, D M, L, K, R
R
básico K, Q, H S, T, E, D, A,
19
imagen21
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Tabla 15: Sustitución para conferir alta afinidad para pKA en KuDoms
Posición
Preferido Permitido Improbable que funcione
10
Asp, Glu Ala, Gly, Ser, Thr Lys, Asn, (Arg, Cys, Phe, His, Ile, Leu, Met, Pro, Gln, Val, Trp, Tyr)
11
Asp, Gly, Ser, Val Glu, Leu, Met, [Asn, Ile, Ala, Thr] (Cys, Phe, His, Lys, Pro, Gln, Arg, Trp, Tyr)
12
Gly (Otros aminoácidos SÓLO si el disulfuro C14-C38 se reemplaza con otros aminoácidos) imagen22
13
Arg, His, Pro, Asn, Ser [Thr, Ala, Gly, Lys, Gln] Phe, Tyr, Cys, Leu, Ile, Val, Asp (Glu, Met, Trp)
14
Cys (Otros aminoácidos SÓLO si C38 también cambió.) imagen23
15
Arg, Lys [Ala, Ser, Gly, Met, Asn, Gln] (Cys, Asp, Glu, Phe, His, Ile, Leu, Pro, Thr, Val, Trp, Tyr)
16
Ala, Gly [Ser, Asp, Asn] (Cys, Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Gln, Arg, Thr, Val, Trp, Tyr)
17
Ala, Asn, Ser, Ile [Gly, Val, Gln, Thr Cys, Asp, Phe, His, Pro, Arg, Tyr, (Glu, Lys, Met, Trp)
18
His, Leu, Gln [Ala, Cys, Asp, Glu, Phe, Gly, Ile, Lys, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, Tyr
19
Pro, Gln, Leu [Asn, Ile] Ala, Glu, Gly, Met, Arg, Ser, Thr, Val, Trp, (Cys, Asp, Phe, His, Tyr)
20
Arg Leu, Ala, Ser, Lys, Gln, Val (Cys, Asp, Glu, Phe, Gly, His, Ile, Met, Asn, Pro, Thr, Trp, Tyr)
21
Trp, Phe [Tyr, His, Ile] Cys, Leu (Ala, Asp, Glu, Gly, Lys, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val)
31
Glu [Asp, Gln, Asn, Ser, Ala, Val, Leu, Ile, Thr] (Arg, Lys, Cys, Phe, Gly, His, Met, Pro, Trp, Tyr)
32
Glu, Gln [Asp, Asn, Pro, Thr, Leu, Ser, Ala, Gly, Val] (Cys, Phe, His, Ile, Lys, Met, Arg, Trp, Tyr)
33
Phe [Tyr] otro 18 excluido
34
Ser, Thr, Ile [Val, Ala, Asn, Gly, Leu] Cys, Asp, Glu, Phe, His, Lys, Met, Pro, Gln, Arg, Trp, Tyr
35
Tyr [Trp, Phe] (otro 17)
36
Gly Ser, Ala (otro 17)
37
Gly (Otros tipos de aminoácidos permitidos solo si C14-C38 se reemplaza con otros tipos.) imagen24
38
Cys (Otros aminoácidos SÓLO si C14 cambió también) imagen25
39
Gly, Glu, Ala [Ser, Asp] Otro 15.
Bajo "Preferido", se subraya el tipo más altamente preferido Bajo "Permitido" están los tipos no probados actuablemente, pero que se juzgan como aceptables. Tipos mostrados entre corchetes se permiten pero no se seleccionaron, pero son similares a los tipos que se seleccionaron del tipo que es improbable que elimine la unión a pKA. Tales tipos no son preferidos, pero las proteínas de unión a pKA pueden tener esos tipos. Bajo" Improbable que funcione", los tipos que se muestran fuera de paréntesis, han sido juzgados y no se tienen aislamientos de ese tipo; los tipos en paréntesis no se probaron, pero se juzgan como inadecuados a partir de la consideración de los tipos actualmente excluidos
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ES10164197.5T 1994-01-11 1995-01-11 Proteínas de dominio Kunitz inhibidores de calicreína y ácidos nucleicos que codifican las mismas Expired - Lifetime ES2514615T3 (es)

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US20060264603A1 (en) 2006-11-23
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US6057287A (en) 2000-05-02
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US8283321B2 (en) 2012-10-09

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