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AR084969A1 - TFPI INHIBITORS AND METHODS OF USE - Google Patents

TFPI INHIBITORS AND METHODS OF USE

Info

Publication number
AR084969A1
AR084969A1 ARP110102360A ARP110102360A AR084969A1 AR 084969 A1 AR084969 A1 AR 084969A1 AR P110102360 A ARP110102360 A AR P110102360A AR P110102360 A ARP110102360 A AR P110102360A AR 084969 A1 AR084969 A1 AR 084969A1
Authority
AR
Argentina
Prior art keywords
group
amino acid
acid selected
aib
tfpi
Prior art date
Application number
ARP110102360A
Other languages
Spanish (es)
Original Assignee
Baxter Int
Baxter Healthcare Sa
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
Priority claimed from PCT/US2011/024604 external-priority patent/WO2011115712A2/en
Application filed by Baxter Int, Baxter Healthcare Sa filed Critical Baxter Int
Publication of AR084969A1 publication Critical patent/AR084969A1/en

Links

Classifications

    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02WCLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W90/00Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
    • Y02W90/10Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics

Landscapes

  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Reivindicación 1: Un péptido que une TFPI, caracterizado porque comprende la estructura de fórmula:X4001-Q-X4003-X4004-X4005-X4006-X4007-X4008-X4009-X4010-X4011-X4012-X4013-X4014-R-X4016-X4017-X4018-X4019-X4020 donde X4001 es un aminoácido seleccionado del grupo que consiste en F, L, M, Y, 1Ni, Thi, Bta, y Dopa; donde X4003 es un aminoácido seleccionado del grupo que consiste en C, D, E, M, Q, R, S, T, Ede(O), y Cmc; donde X4004 es un aminoácido seleccionado del grupo que consiste en Aib, E, G, l, K, L, M, P, R, W, e Y; donde X4005 es un aminoácido seleccionado del grupo que consiste en a, A, Aib, C, D, d, E, G, H, K, k, M, N, Nmg, p, Q, R, NpropilG, aze, pip, tic, oic, hyp, nma, Ncg, Abg, Apg, thz, y dtc; donde X4006 es un aminoácido seleccionado del grupo que consiste en A, C, C(NEM), D, E, G, H, K, M, N, Q, R, S, V, Cit, C(Acm), Nle, I, Ede(O), Cmc, EcI, Eea, Eec, Eef, Nif, y Eew; donde X4007 es un aminoácido seleccionado del grupo que consiste en I, V, T, Chg, Phg, y TIe; donde X4008 es un aminoácido seleccionado del grupo que consiste en F, H, 1Ni, 2Ni, Pmy, e Y; donde X4009 es un aminoácido seleccionado del grupo que consiste en Aib, V, Chg, Phg, Abu, Cpg, TIe, y ácido L-2-amino-4,4,4-trifluorobutírico; donde X4010 es un aminoácido seleccionado del grupo que consiste en A, C, D, d, E, F, H, K, M, N, P, Q, R, S, T, V, W, Y, Nmd, y C(NEM); donde X4011 es un aminoácido seleccionado del grupo que consiste en A, a, G, p, Sar, c, y hcy; donde X4012 es un aminoácido seleccionado del grupo que consiste en Y, Tym, Pty, Dopa, y Pmy; donde X4013 es un aminoácido seleccionado del grupo que consiste en C, F, 1Ni, Thi, y Bta; donde X4014 es un aminoácido seleccionado del grupo que consiste en A, Aib, C, C(NEM), D, E, K, L, M, N, Q, R, T, V, y Hcy; donde X4016 es un aminoácido seleccionado del grupo que consiste en L, Hcy, HIe, y AmI; donde X4017 es un aminoácido seleccionado del grupo que consiste en A, a, Aib, C, c, Cha, Dab, Eag, Eew, H, Har, Hci, HIe, I, K, L, M, Nle, Nva, Opa, Orn, R, S, Deg, Ebc, Eca, Egz, Aic, Apc, y Egt; donde X4018 es un aminoácido seleccionado del grupo que consiste en A, Aib, Hcy, hcy, C, c, L, Nle, M, N, y R; donde X4019 es un aminoácido seleccionado del grupo que consiste en K, R, y Har; y donde X4020 es un aminoácido seleccionado del grupo que consiste en K, L, Hcy, y Aml; y donde el péptido no comprende la siguiente estructura de fórmula: X5001-Q-X5003-X5004-X5005-X5006-I/V-X5008-Aib/V-X5010-G-Y-X5013-X5014-R-L-X5017-X5018-K-K/L donde X5001 es un aminoácido seleccionado del grupo que consiste en F, L, M, e Y; donde X5003 es un aminoácido seleccionado del grupo que consiste en C, D, E, M, Q, R, S, y T; donde X5004 es un aminoácido seleccionado del grupo que consiste en E, G, I, K, L, M, P, R, W, e Y; donde X5005 es un aminoácido seleccionado del grupo que consiste en a, A, Aib, C, D, d, E, G, H, K, k, M, N, Nmg, Q, R, y p; donde X5006 es un aminoácido seleccionado del grupo que consiste en A, C, D, E, G, H, K, M, N, Q, R, S, y V; donde X5008 es un aminoácido seleccionado del grupo que consiste en F, H, e Y; donde X5010 es un aminoácido seleccionado del grupo que consiste en A, C, D, E, F, H, D, M, N, P, Q, R, S, T, V, W, e Y; donde X5013 es un aminoácido seleccionado del grupo que consiste en Aib, C, y F; donde X5014 es un aminoácido seleccionado del grupo que consiste en A, Aib, C, D, E, K, L, M, N, Q, R, T, y V; donde X5017 es un aminoácido seleccionado del grupo que consiste en A, Aib, C, Cha, Dab, Eag, Eew, H, Har, Hci, Hle, I, K, L, M, NIe, Nve, Opa, Orn, R, y S; y donde X5018 es un aminoácido seleccionado del grupo que consiste en A, C, L, M, N, y R. Reivindicación 27: Uso del péptido de acuerdo con cualquiera de las reivindicaciones 1 - 5, 16, ó 17 para la fabricación de un medicamento para el tratamiento de un trastorno de coagulación de la sangre. Reivindicación 41: Un método para tratar un sujeto que sufre de una enfermedad o tiene riesgo de sufrir una enfermedad, el método que comprende administrar al sujeto el péptido de cualquiera de las reivindicaciones 1 - 5, 16, ó 17, y administrar al sujeto un compañero de interacción que (a) se une al péptido y (b) es un agente terapéutico o se conjuga a un agente terapéutico. Reivindicación 54: Un método para purificar TFPI, caracterizado porque el método comprende a) poner en contacto una muestra que contiene TFPI con el péptido de cualquiera de las reivindicaciones 1 - 5, 16, ó 17 en condiciones apropiadas para formar un complejo entre TFPI y el péptido; b) extraer el complejo de la muestra; y, opcionalmente, c) disociar el complejo para liberar TFPI. Reivindicación 86: Un método para purificar un compuesto que inhibe la actividad de FXa, el método caracterizado porque comprende (a) poner en contacto un péptido que comprende el dominio 1 de Kunitz de TFPI (KD1) con un compuesto en condiciones que permiten la formación de complejos compuesto-KD1, (b) eliminar compuesto no unido, y (c) disociar los complejos compuesto-KD1 para liberar el compuesto. Reivindicación 88: Un medio de almacenamiento de computadora que tiene instrucciones ejecutables por computadora que, cuando se ejecuta en el procesador de una computadora, implementa un método de modelado de la interacción entre los puntos tridimensionales (3D) seleccionados en una proteína del dominio 1 de Kunitz de TFPI (KD1) y un compuesto de ensayo, el método que comprende: obtener un modelo de estructura 3D de una proteína para la proteína TFPI KD1; determinar una relación 3D entre un subconjunto seleccionado de aminoácidos en la estructura de la proteína, donde el subconjunto seleccionado de aminoácidos comprende Phe28, Lys29, Ala30, Asp32, Ile46, Phe47, e Ile55; modelar una superficie unida con el subconjunto seleccionado de aminoácidos; obtener un modelo 3D del compuesto de ensayo de un compuesto de ensayo; hacer coincidir el modelo 3D del compuesto de ensayo con la superficie unida con el subconjunto seleccionado de aminoácidos; e identificar puntos de contacto entre el subconjunto seleccionado de aminoácidos de la superficie y el modelo 3D del compuesto de ensayo.Claim 1: A peptide that binds TFPI, characterized in that it comprises the structure of the formula: X4001-Q-X4003-X4004-X4005-X4006-X4007-X4008-X4009-X4010-X4011-X4012-X4013-X4014-R-X4016-X4017 -X4018-X4019-X4020 where X4001 is an amino acid selected from the group consisting of F, L, M, Y, 1Ni, Thi, Bta, and Dopa; where X4003 is an amino acid selected from the group consisting of C, D, E, M, Q, R, S, T, Ede (O), and Cmc; where X4004 is an amino acid selected from the group consisting of Aib, E, G, l, K, L, M, P, R, W, and Y; where X4005 is an amino acid selected from the group consisting of a, A, Aib, C, D, d, E, G, H, K, k, M, N, Nmg, p, Q, R, NpropilG, aze, pip , tic, oic, hyp, nma, Ncg, Abg, Apg, thz, and dtc; where X4006 is an amino acid selected from the group consisting of A, C, C (NEM), D, E, G, H, K, M, N, Q, R, S, V, Cit, C (Acm), Nle , I, Ede (O), Cmc, EcI, Eea, Eec, Eef, Nif, and Eew; where X4007 is an amino acid selected from the group consisting of I, V, T, Chg, Phg, and TIe; where X4008 is an amino acid selected from the group consisting of F, H, 1Ni, 2Ni, Pmy, and Y; where X4009 is an amino acid selected from the group consisting of Aib, V, Chg, Phg, Abu, Cpg, TIe, and L-2-amino-4,4,4-trifluorobutyric acid; where X4010 is an amino acid selected from the group consisting of A, C, D, d, E, F, H, K, M, N, P, Q, R, S, T, V, W, Y, Nmd, and C (NEM); where X4011 is an amino acid selected from the group consisting of A, a, G, p, Sar, c, and hcy; where X4012 is an amino acid selected from the group consisting of Y, Tym, Pty, Dopa, and Pmy; where X4013 is an amino acid selected from the group consisting of C, F, 1Ni, Thi, and Bta; where X4014 is an amino acid selected from the group consisting of A, Aib, C, C (NEM), D, E, K, L, M, N, Q, R, T, V, and Hcy; where X4016 is an amino acid selected from the group consisting of L, Hcy, HIe, and AmI; where X4017 is an amino acid selected from the group consisting of A, a, Aib, C, c, Cha, Dab, Eag, Eew, H, Har, Hci, HIe, I, K, L, M, Nle, Nva, Opa , Orn, R, S, Deg, Ebc, Eca, Egz, Aic, Apc, and Egt; where X4018 is an amino acid selected from the group consisting of A, Aib, Hcy, hcy, C, c, L, Nle, M, N, and R; where X4019 is an amino acid selected from the group consisting of K, R, and Har; and where X4020 is an amino acid selected from the group consisting of K, L, Hcy, and Aml; and where the peptide does not comprise the following formula structure: X5001-Q-X5003-X5004-X5005-X5006-I / V-X5008-Aib / V-X5010-GY-X5013-X5014-RL-X5017-X5018-KK / L where X5001 is an amino acid selected from the group consisting of F, L, M, and Y; where X5003 is an amino acid selected from the group consisting of C, D, E, M, Q, R, S, and T; where X5004 is an amino acid selected from the group consisting of E, G, I, K, L, M, P, R, W, and Y; where X5005 is an amino acid selected from the group consisting of a, A, Aib, C, D, d, E, G, H, K, k, M, N, Nmg, Q, R, and p; where X5006 is an amino acid selected from the group consisting of A, C, D, E, G, H, K, M, N, Q, R, S, and V; where X5008 is an amino acid selected from the group consisting of F, H, and Y; where X5010 is an amino acid selected from the group consisting of A, C, D, E, F, H, D, M, N, P, Q, R, S, T, V, W, and Y; where X5013 is an amino acid selected from the group consisting of Aib, C, and F; where X5014 is an amino acid selected from the group consisting of A, Aib, C, D, E, K, L, M, N, Q, R, T, and V; where X5017 is an amino acid selected from the group consisting of A, Aib, C, Cha, Dab, Eag, Eew, H, Har, Hci, Hle, I, K, L, M, NIe, Nve, Opa, Orn, R , and S; and wherein X5018 is an amino acid selected from the group consisting of A, C, L, M, N, and R. Claim 27: Use of the peptide according to any one of claims 1-5, 16, or 17 for the manufacture of a medication for the treatment of a blood clotting disorder. Claim 41: A method of treating a subject suffering from a disease or at risk of suffering from a disease, the method comprising administering to the subject the peptide of any one of claims 1-5, 16, or 17, and administering to the subject a interaction partner that (a) binds to the peptide and (b) is a therapeutic agent or conjugates to a therapeutic agent. Claim 54: A method for purifying TFPI, characterized in that the method comprises a) contacting a sample containing TFPI with the peptide of any of claims 1-5, 16, or 17 under appropriate conditions to form a complex between TFPI and the peptide; b) extract the sample complex; and, optionally, c) dissociate the complex to release TFPI. Claim 86: A method for purifying a compound that inhibits FXa activity, the method characterized in that it comprises (a) contacting a peptide comprising the Kunitz domain 1 of TFPI (KD1) with a compound under conditions that allow formation of compound-KD1 complexes, (b) remove unbound compound, and (c) dissociate the compound-KD1 complexes to release the compound. Claim 88: A computer storage medium having computer-executable instructions that, when executed in a computer's processor, implements a method of modeling the interaction between the three-dimensional (3D) points selected in a domain 1 domain protein. Kunitz of TFPI (KD1) and a test compound, the method comprising: obtaining a 3D structure model of a protein for the TFPI KD1 protein; determine a 3D relationship between a selected subset of amino acids in the protein structure, where the selected subset of amino acids comprises Phe28, Lys29, Ala30, Asp32, Ile46, Phe47, and Ile55; model a bound surface with the selected subset of amino acids; obtain a 3D model of the test compound of a test compound; matching the 3D model of the test compound with the surface attached to the selected subset of amino acids; and identify contact points between the selected subset of surface amino acids and the 3D model of the test compound.

ARP110102360A 2011-02-11 2011-06-30 TFPI INHIBITORS AND METHODS OF USE AR084969A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US2011/024604 WO2011115712A2 (en) 2010-03-19 2011-02-11 Tfpi inhibitors and methods of use
US13/026,070 US8450275B2 (en) 2010-03-19 2011-02-11 TFPI inhibitors and methods of use

Publications (1)

Publication Number Publication Date
AR084969A1 true AR084969A1 (en) 2013-07-24

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ARP110102360A AR084969A1 (en) 2011-02-11 2011-06-30 TFPI INHIBITORS AND METHODS OF USE

Country Status (2)

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AR (1) AR084969A1 (en)
TW (1) TWI483733B (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2379096B1 (en) * 2008-12-19 2019-10-30 Baxalta GmbH Tfpi inhibitors and methods of use

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Publication number Publication date
TWI483733B (en) 2015-05-11
TW201233394A (en) 2012-08-16

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