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    Activated protein C variants with normal cytoprotective activity but reduced anticoagulant activity
    2.
    发明授权
    Activated protein C variants with normal cytoprotective activity but reduced anticoagulant activity 有权
    具有正常细胞保护活性但具有降低的抗凝血活性的活化蛋白C变体

    公开(公告)号：US09192657B2

    公开(公告)日：2015-11-24

    申请号：US11589371

    申请日：2006-10-30

    申请人： John H. Griffin ,  Laurent O. Mosnier ,  Andrew J. Gale

    发明人： John H. Griffin ,  Laurent O. Mosnier ,  Andrew J. Gale

    IPC分类号： A61K38/48 ,  C12N9/64

    CPC分类号： A61K38/4866 ,  C12N9/6464 ,  C12Y304/21069

    摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.

    摘要翻译： 提供重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其具有显着降低抗凝血活性，但保持正常水平的抗凋亡活性。 这些重组APC突变体的三个实例是KKK191-193AAA-APC，RR229 / 230AA-APC和RR229 / 230AA加上KKK191-193AAA-APC。 本发明的APC变体和前药具有细胞保护性（抗凋亡作用）的期望性质，同时具有显着降低的出血风险。 本发明还提供了使用本发明的APC变体或前药来治疗受益于APC的细胞保护活性而不受APC抗凝活性影响的受试者的方法。 这些受试者包括至少部分地通过细胞凋亡而导致各种器官的血管损伤或组织损伤风险的患者。 在危险中，患者包括例如患有（严重）败血症，缺血/再灌注损伤，缺血性卒中，急性心肌梗死，急性或慢性神经变性疾病或经历器官移植或化疗的患者等。 还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

    Protein S protects the nervous system from injury
    3.
    发明授权
    Protein S protects the nervous system from injury 失效
    蛋白S可保护神经系统免受伤害

    公开(公告)号：US07968515B2

    公开(公告)日：2011-06-28

    申请号：US10529748

    申请日：2003-09-30

    申请人： Berislav V. Zlokovic ,  John H. Griffin

    发明人： Berislav V. Zlokovic ,  John H. Griffin

    IPC分类号： A61K38/36

    CPC分类号： C07K14/8128 ,  A61K38/36 ,  G01N2500/10 ,  G01N2510/00

    摘要： Protein S is a significant neuroprotectant when administered after focal ischemic stroke and prevents hypoxic/re-oxygenation injury. Purified human plasma-derived or recombinant protein S improves motor neurological function after stroke, and reduced brain infarction and edema. Protein S also enhances post-ischemic reperfusion and reduced brain fibrin and neutrophil deposition. Cortical neurons are protected from hypoxia/re-oxygenation-induced apoptosis. Thus, protein S and variants thereof are prototypes of a class of agents for preventing injury of the nervous system. In particular, a disease or other pathological condition (e.g., stroke) may be treated with such agents having one or more protein S activities (e.g., anti-thrombotic and anti-inflammatory activities, direct cellular neuronal protective effects) although the latter activities are not be required.

    摘要翻译： 当局部缺血性中风后施用时，蛋白S是一种显着的神经保护剂，可预防缺氧/再氧合损伤。 纯化的人血浆来源或重组蛋白S改善中风后的运动神经功能，减少脑梗塞和水肿。 蛋白S还增强了缺血后再灌注并减少了脑纤维蛋白和嗜中性粒细胞沉积。 皮质神经元被保护免受缺氧/再氧合诱导的细胞凋亡。 因此，蛋白质S及其变体是用于预防神经系统损伤的一类试剂的原型。 特别地，可以用具有一种或多种蛋白S活性（例如，抗血栓形成和抗炎活性，直接细胞神经元保护作用）的药物治疗疾病或其它病理状况（例如中风），尽管后一种活性是 不需要。

    DOSING REGIMEN OF ACTIVATED PROTEIN C AND VARIANTS HAVING REDUCED ANTICOAGULANT ACTIVITY
    4.
    发明申请
    DOSING REGIMEN OF ACTIVATED PROTEIN C AND VARIANTS HAVING REDUCED ANTICOAGULANT ACTIVITY 审中-公开
    活化蛋白C的剂量和具有降低抗血小板活性的变体

    公开(公告)号：US20100284997A1

    公开(公告)日：2010-11-11

    申请号：US12447845

    申请日：2007-10-31

    申请人： John H. Griffin ,  Hartmut Weiler

    发明人： John H. Griffin ,  Hartmut Weiler

    IPC分类号： A61K38/48 ,  C12N9/48 ,  A61P31/04 ,  A61P7/02

    CPC分类号： A61K38/4866

    摘要： Recombinant activated protein C (APC) and APC variants with reduced anticoagulant activity were used to reduce mortality in murine models of sepsis. These models included endotoxemia and bacteremia models. We discovered that single or multiple bolus doses of APC, especially of APC variants such as RR230/231AA-APC, KKK192-194AAA-APC and 5A-APC (containing the combination of mutations present in the first two APC variants) given as a single bolus reduces 7-day mortality of mice given lethal doses of endotoxin. Administrations of a single bolus of 5A-APC after the initiation of sepsis also reduces mortality caused by LPS. 5A-APC with ≦8% of normal anticoagulant activity (which has reduced risk of bleeding) reduces mortality when given as two bolus administrations at 3 hours and then at 10 hours after initiation of bacterial infection, i.e. after onset of sepsis. This shows, first, that one or more bolus injections of APC or of APC variants, especially 5A-APC, can reduce mortality when given beginning hours after the onset of sepsis and, second, that it is not necessary to administer APC as a continuous infusion which is the current standard of practice because one or more bolus administrations can reduce mortality. Furthermore, dosages of approximately 0.06 to 0.4 mg/kg of APC and APC variants are identified to be sufficient to reduce mortality in sepsis.

    摘要翻译： 使用具有降低的抗凝活性的重组活化蛋白C（APC）和APC变体降低脓毒病鼠模型的死亡率。 这些模型包括内毒素血症和菌血症模型。 我们发现单次或多次推注剂量的APC，特别是APC变体如RR230 / 231AA-APC，KKK192-194AAA-APC和5A-APC（含有前两个APC变体中存在的突变的组合）作为单一 推注减少给予致死剂量的内毒素的小鼠的7天死亡率。 开始脓毒症后单次推注5A-APC的主管部门也降低了LPS引起的死亡率。 具有正常抗凝活性（降低出血风险）的8％的正常抗凝活性的8％在3小时，然后在细菌感染开始后10小时（即败血症发作后）作为两次推注给药时降低死亡率。 这显示，首先，APC或APC变体，特别是5A-APC的一次或多次推注注射可以在脓毒症发作开始后几小时减少死亡率，其次，不必将APC作为连续的 输注是目前的实践标准，因为一次或多次推注给药可以降低死亡率。 此外，鉴定了大约0.06至0.4mg / kg APC和APC变体的剂量足以降低败血症的死亡率。

    Novel antibacterial agents
    5.
    发明申请
    Novel antibacterial agents 审中-公开
    新型抗菌剂

    公开(公告)号：US20090111737A1

    公开(公告)日：2009-04-30

    申请号：US12082666

    申请日：2008-04-11

    申请人： Burton G. Christensen ,  Edmund J. Moran ,  John H. Griffin ,  J. Kevin Judice ,  YongQi Mu ,  John L. Pace ,  Mathai Mammen ,  James Aggen

    发明人： Burton G. Christensen ,  Edmund J. Moran ,  John H. Griffin ,  J. Kevin Judice ,  YongQi Mu ,  John L. Pace ,  Mathai Mammen ,  James Aggen

    IPC分类号： A61K38/14 ,  C07K7/00 ,  A61P43/00

    CPC分类号： C07D477/12 ,  C07D499/32 ,  C07D499/44 ,  C07D501/56

    摘要： This invention relates to novel multibinding compounds (agents) that are antibacterial agents. The multibinding compounds of the invention comprise from 2-10 ligands covalently connected by a linker or linkers, wherein each of said ligands in their monovalent (i.e., unlinked) state have the ability to bind to a an enzyme involved in cell wall biosynthesis and metabolism, a precursor used in the synthesis of the bacterial cell wall and/or the bacterial cell surface thereby interfere with the synthesis and/or metabolism of the cell wall. In particular the multibinding compounds of the invention comprise from 2-10 ligands covalently connected by a linker or linkers, wherein each of said ligands has a ligand domain capable of binding to penicillin binding proteins, a transpeptidase enzyme, a substrate of a transpeptidase enzyme, a beta-lactamase enzyme, pencillinase enzyme, cephalosporinase enzyme, a transglycoslase enzyme, or a transglycosylase enzyme substrate; Preferably, the ligands are selected from the beta lactam or glycopeptide class of antibacterial agents.

    摘要翻译： 本发明涉及作为抗菌剂的新型多结合化合物（试剂）。 本发明的多相结合化合物包含2-10个配体，其通过连接体或连接体共价连接，其中所述各单体（即，未连接）状态的所述配体具有结合涉及细胞壁生物合成和代谢的酶的能力 用于合成细菌细胞壁和/或细菌细胞表面的前体因而干扰细胞壁的合成和/或代谢。 特别地，本发明的多相结合化合物包含通过接头或接头共价连接的2-10个配体，其中每个所述配体具有能够结合青霉素结合蛋白的配体结构域，转肽酶，转肽酶的底物， β-内酰胺酶，pencillinase酶，头孢菌素酶，转糖基酶或转糖基酶酶底物; 优选地，配体选自β-内酰胺或糖肽类抗菌剂。

    Stabilized proteins with engineered disulfide bonds
    6.
    发明授权
    Stabilized proteins with engineered disulfide bonds 失效
    具有工程化二硫键的稳定蛋白

    公开(公告)号：US07205278B2

    公开(公告)日：2007-04-17

    申请号：US10172712

    申请日：2002-06-14

    申请人： John H. Griffin ,  Andrew J. Gale ,  Elizabeth D. Getzoff ,  Jean-Luc Pellequer

    发明人： John H. Griffin ,  Andrew J. Gale ,  Elizabeth D. Getzoff ,  Jean-Luc Pellequer

    IPC分类号： A61K38/36 ,  C07K14/475

    CPC分类号： C07K1/1075 ,  A61K38/00 ,  C07K1/107 ,  C07K14/745 ,  C07K14/755

    摘要： The present invention relates to methods of introducing one or more cysteine residues into a polypeptide which permit the stabilization of the polypeptide by formation of at least one bond, preferably a disulfide bond, between different domains of the polypeptide. The invention also relates to polypeptides containing such introduced cysteine residue(s), nucleic acids encoding such polypeptides and pharmaceutical compositions comprising such polypeptides or nucleic acids. The invention also relates to vectors, viral particles and host cells containing such nucleic acids, and methods of using them to produce the polypeptides of the invention. Exemplified polypeptides include plasma proteins, including hepatocyte growth factor activator and plasma hyaluronin binding protein, as well as blood coagulation factors, such as Factor VIII, Factor V, Factor XII and prothrombin.

    摘要翻译： 本发明涉及将一种或多种半胱氨酸残基引入多肽的方法，所述多肽允许通过在多肽的不同结构域之间形成至少一个键，优选二硫键来稳定多肽。 本发明还涉及含有这种引入的半胱氨酸残基的多肽，编码这些多肽的核酸和包含这种多肽或核酸的药物组合物。 本发明还涉及含有这种核酸的载体，病毒颗粒和宿主细胞，以及使用它们产生本发明多肽的方法。 示例性多肽包括血浆蛋白，包括肝细胞生长因子激活剂和血浆透明质酸结合蛋白，以及凝血因子，如因子VIII，因子V，因子XII和凝血酶原。

    Protease Activated Receptor-1 (PAR1) Derived Cytoprotective Polypeptides and Related Methods
    10.
    发明授权
    Protease Activated Receptor-1 (PAR1) Derived Cytoprotective Polypeptides and Related Methods 有权

    公开(公告)号：US09605046B2

    公开(公告)日：2017-03-28

    申请号：US14356692

    申请日：2012-11-07

    申请人： THE SCRIPPS RESEARCH INSTITUTE ,  Laurent O. Mosnier ,  John H. Griffin

    发明人： Laurent O. Mosnier ,  John H. Griffin

    IPC分类号： A61K38/00 ,  A61P5/00 ,  C07K14/705 ,  A61K38/17

    CPC分类号： C07K14/705 ,  A61K38/00 ,  A61K38/177

    摘要： The present invention provides novel PAR 1 derived cytoprotective oligopeptides or polypeptides which typically contain at least the first 4 N-terminal residues that are substantially identical to the corresponding N-terminal residues of Met1-Arg46 deleted human PAR 1 sequence. These cytoprotective oligopeptides or polypeptides are capable of activating PAR 1 and promoting PAR 1 cytoprotective signaling activities. The invention also provides engineered cells or transgenic non-human animals which harbor in their genome an altered PAR 1 gene that is resistant to cleavage at Arg41 and/or Arg46 residues. Additionally provided in the invention are methods of screening candidate compounds to identity additional cytoprotective compounds or cytoprotective proteases. The invention further provides therapeutic use or methods of employing a PAR 1 derived cytoprotective oligopeptide or polypeptide to treat conditions associated with tissue injuries or undesired apoptosis.