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11.发明授权Short amphipathic peptides with activity against bacteria and intracellular pathogens 失效具有抗细菌和细胞内病原体活性的短两亲肽公开(公告)号：US07262163B2
公开(公告)日：2007-08-28
申请号：US10414342
申请日：2003-04-14
申请人： Mark L. McLaughlin , Thomas S. Yokum , Frederick M. Enright , Philip H. Elzer , Robert P. Hammer
发明人： Mark L. McLaughlin , Thomas S. Yokum , Frederick M. Enright , Philip H. Elzer , Robert P. Hammer
CPC分类号： C07K7/06 , A61K38/00 , C07K7/08 , Y02A50/402 , Y02A50/481 , Y10S977/903
摘要： “Minimalist” antimicrobial peptides are disclosed based on 50 to 80% α,α-dialkylated amino acids. The peptides are short, cationic, amphipathic, and possess a high helix propensity. Polar α,α-dialkylated amino acids are also disclosed. These peptides are easy and inexpensive to synthesize via solid-phase techniques. The peptides exhibit in vitro anti-bacterial properties at concentrations that are not lethal to normal mammalian cells. The peptides exhibit in vivo bioactivity against intracellular pathogens.
摘要翻译： 基于50至80％的α，α-二烷基化氨基酸公开了“极简”抗微生物肽。 肽短，阳离子，两亲，具有高螺旋倾向。 还公开了极性α，α-二烷基化氨基酸。 这些肽通过固相技术合成是容易和便宜的。 这些肽在不对正常哺乳动物细胞致死的浓度下表现出体外抗细菌特性。 肽表现出体内对细胞内病原体的生物活性。
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12.发明授权公开(公告)号：US06264952B1
公开(公告)日：2001-07-24
申请号：US08989089
申请日：1997-12-11
IPC分类号： A61K3900
CPC分类号： A61K39/098 , Y02A50/41 , Y10S424/823 , Y10S424/824 , Y10S435/822
摘要： Vaccines against facultative intracellular pathogens are disclosed. A host is vaccinated with non-viable but metabolically active agents. The non-viable agents produce immunogenic components that elicit protective host immune responses, with minimal likelihood of host infection by the vaccine agent. Living agents, either attenuated or virulent, are exposed to a dose of gamma irradiation (or other strong mutagen) that is sufficient to limit or prevent the replication of the agents within the host, but that is insufficient to stop the metabolic activities of the agent. In vitro exposure of a microbial agent to the damaging effects of gamma irradiation or of another strong mutagen induces certain stress responses in the infectious agent. These stress responses are similar to the stress responses that the virulent agent would produce within the tissues of the host. The stress responses include the production of antigens that stimulate appropriate host immune responses when the irradiated agent is used in a vaccine. Examples of facultative intracellular pathogens for which non-viable vaccine agents may be made in accordance with the present invention include various bacterial pathogens (e.g., Brucella sp., Brucella abortus, Mycobacterium sp., Mycobacteriun lepraemurum, Mycobacterium tuberculosis, Salmonella sp., Salmonella typhimurium); various mycotic pathogens (e.g., Blastomyces, Histoplasma, Cocidioides); and various protozoal pathogens (e.g., Leishmania, Trypanosomas).
摘要翻译： 公开了针对兼性细胞内病原体的疫苗。 宿主接种了不可行但代谢活性的药物。 不存活的试剂产生免疫原性成分，引发保护性宿主免疫反应，宿主感染疫苗的可能性最小。 减毒或有毒的活性剂暴露于足以限制或防止宿主内药物复制的γ照射剂量（或其他强诱变剂），但不足以阻止药剂的代谢活性 。 微生物剂体外暴露于γ照射或另一种强诱变剂的损伤作用会在感染剂中引起某些应激反应。 这些应激反应类似于毒素在宿主组织内产生的应激反应。 应激反应包括在将疫苗用于疫苗时刺激适当的宿主免疫应答的抗原的产生。 可根据本发明制备非活菌疫苗的兼性细胞内病原体的实例包括各种细菌病原体（例如布鲁氏菌属布鲁杆菌，流行性分枝杆菌，分枝杆菌，分枝杆菌，结核分枝杆菌，沙门氏菌，沙门氏菌 鼠伤寒）; 各种真菌病原体（例如，Blastomyces，组织胞浆菌，Cocidioides）; 和各种原生动物病原体（例如，利什曼原虫，锥虫属）。
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13.发明授权公开(公告)号：US06680058B1
公开(公告)日：2004-01-20
申请号：US09486143
申请日：2000-02-22
申请人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Patricia A. Melrose , Philip H. Elzer
发明人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Patricia A. Melrose , Philip H. Elzer
IPC分类号： A61K3824
CPC分类号： C07K19/00 , A61K38/24 , C07K7/23 , C07K14/43563 , C07K14/575 , C07K14/59 , C07K2319/00 , Y10S514/841 , Y10S514/843 , A61K2300/00
摘要： Amphipathic lytic peptides are ideally suited to use in a ligand/cytotoxin combination to induce sterility or long-term contraception in mammals. The peptides act directly on cell membranes, and need not be internalized. Administering a combination of gonadotropin-releasing hormone (GnRH) (or a GnRH agonist) and a membrane-active lytic peptide produces long-term contraception or sterilization in mammals in vivo. The compounds are relatively small, and are not antigenic. Lysis of gonadotropes has been observed to be very rapid (on the order of ten minutes.) The two components—the ligand and the lytic peptide—may optionally be administered as a fusion peptide, or they may be administered separately, with the ligand administered slightly before the lytic peptide, to activate cells with receptors for the ligand, and thereby make those cells susceptible to lysis by the lytic peptide.
摘要翻译： 两亲性裂解肽理想地适用于配体/细胞毒素组合以诱导哺乳动物的不育或长期避孕。 肽直接作用于细胞膜上，不需要内化。 管理促性腺激素释放激素（GnRH）（或GnRH激动剂）和膜活性溶解肽的组合在哺乳动物体内产生长期避孕或灭菌。 化合物相对较小，不具抗原性。 已经观察到促性腺激素的裂解非常快（十分钟左右）。配体和裂解肽的两个组分可以任选地作为融合肽施用，或者它们可以单独给药，配体给予 在溶解肽之前稍微激活具有配体受体的细胞，从而使这些细胞易溶解裂解肽。
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公开(公告)号：US06635740B1
公开(公告)日：2003-10-21
申请号：US09381879
申请日：1999-09-24
申请人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Kenneth L. Koonce , Samuel M. McCann , Wen H. Yu , Patricia A. Melrose , Lane D. Foil , Philip H. Elzer
发明人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Kenneth L. Koonce , Samuel M. McCann , Wen H. Yu , Patricia A. Melrose , Lane D. Foil , Philip H. Elzer
IPC分类号： C07K1400
CPC分类号： C12N15/8257 , A61K38/00 , C07K7/23 , C07K14/43563 , C07K14/575 , C07K14/59 , C07K19/00 , C07K2319/00
摘要： Amphipathic lytic peptides are ideally suited to use in a ligand/cytotoxin combination to specifically inhibit cells that are driven by or are dependent upon a specific ligand interaction; for example, to induce sterility or long-term contraception, or to attack tumor cells, or to selectively lyse virally-infected cells, or to attack lymphocytes responsible for autoimmune diseases. The peptides act directly on cell membranes, and need not be internalized. Administering a combination of gonadotropin-releasing hormone (GnRH) (or a GnRH agonist) and a membrane-active lytic peptide produces long-term contraception or sterilization in animals in vivo. Administering in vivo a combination of a ligand and a membrane-active lytic peptide kills cells with a receptor for the ligand. The compounds are relatively small, and are not antigenic. Lysis of gonadotropes has been observed to be very rapid (on the order of ten minutes.) Lysis of tumor cells is rapid. The two components—the ligand and the lytic peptide—may optionally be administered as a fusion peptide, or they may be administered separately, with the ligand administered slightly before the lytic peptide, to activate cells with receptors for the ligand, and thereby make those cells susceptible to lysis by the lytic peptide. The compounds may be used in gene therapy to treat malignant or non-malignant tumors, and other diseases caused by clones or populations of “normal” host cells bearing specific receptors (such as lymphocytes), because genes encoding a lytic peptide or encoding a lytic peptide/peptide hormone fusion may readily be inserted into hematopoietic stem cells or myeloid precursor cells.
摘要翻译： 两亲性溶解肽理想地适用于配体/细胞毒素组合以特异性抑制由特定配体相互作用驱动或依赖于特定配体相互作用的细胞; 例如，诱导不育或长期避孕，或攻击肿瘤细胞，或选择性裂解病毒感染的细胞，或攻击负责自身免疫性疾病的淋巴细胞。 肽直接作用于细胞膜上，不需要内化。 管理促性腺激素释放激素（GnRH）（或GnRH激动剂）和膜活性溶解肽的组合在体内产生长期的动物避孕或灭菌。 在体内施用配体和膜活性裂解肽的组合将细胞与配体的受体杀死。 化合物相对较小，不具抗原性。 已经观察到促性腺激素的裂解非常快（十分钟左右）。肿瘤细胞裂解很快。 两种组分 - 配体和溶解肽 - 可以任选地作为融合肽施用，或者它们可以分开施用，配体在裂解肽之前略微施用，以激活具有配体受体的细胞，从而使得 易溶于裂解肽的细胞。 这些化合物可以用于治疗恶性或非恶性肿瘤的基因治疗，以及由具有特异性受体（如淋巴细胞）的“正常”宿主细胞的克隆或群体引起的其它疾病，因为编码溶解肽或编码溶酶体的基因 肽/肽激素融合可容易地插入到造血干细胞或骨髓前体细胞中。
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15.发明授权公开(公告)号：US06303568B1
公开(公告)日：2001-10-16
申请号：US08749066
申请日：1996-11-14
IPC分类号： A61K3800
CPC分类号： C12N1/06 , A01K2217/05 , A61K38/00 , C07K14/43563 , Y02A50/414
摘要： A novel class of antimicrobial agents for animal species including cecropins, attacins, lysozymes, phage derived polypeptides, such as those transcribed from gene 13 of phage 22, an S protein from lambda phage, and an E protein from phage PhiXl74, as well as, synthetically derived polypeptides of similar nature. The antimicrobial agents can be used to treat microbial infections and as components of medicinal compositions. The genes encoding for such antimicrobial agents can be used to transform animal cells, especially embryonic cells. The transformed animals including such antimicrobial cells are also included.
摘要翻译： 用于动物物种的新型抗微生物剂包括天蚕素，attacins，溶菌酶，噬菌体衍生多肽，例如从噬菌体22的基因13转录的那些，来自λ噬菌体的S蛋白和来自噬菌体PhiX174的E蛋白， 合成衍生的具有相似性质的多肽。 抗微生物剂可用于治疗微生物感染和药物组合物的组分。 编码这些抗微生物剂的基因可用于转化动物细胞，特别是胚胎细胞。 包括这些抗菌细胞的转化动物也包括在内。
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公开(公告)号：US6156568A
公开(公告)日：2000-12-05
申请号：US895344
申请日：1997-07-16
CPC分类号： C12N15/85 , C07K14/47 , C12N2800/90 , C12N2830/00 , C12N2830/75
摘要： Novel means have been discovered for increasing the resistance of an animal host (including humans) to diseases caused by intracellular bacteria, protozoa, and viruses. The infection treated may, for example, be equine infectious anemia, or infection by the human immunodeficiency virus. Novel means have also been found for treating tumors. Augmentation of the host's defenses against infectious diseases or tumors is achieved by "arming" the host's cells with an exogenous gene encoding a natural or synthetic lytic peptide. For example, the transfection of hematopoietic stem cells and embryonic cells will produce animals with enhanced disease resistance; and transfection of TIL (tumor infiltrating lymphocytes) cells or other cells can be used in the treatment of tumors. Genes coding for a cecropin or other native or synthetic lytic peptide can be transferred and stably expressed in mammalian, bony fish, other vertebrate, and other animal cells. The transformed cells have the ability to produce and secrete a broad spectrum chemotherapeutic agent that has a systemic effect on certain pathogens, particularly pathogens that might otherwise evade or overcome host defenses. Novel means have also been discovered for transforming a eukaryotic cell with a gene under the control of an exogenous promoter that is responsive to an inducer of an acute-phase peptide or protein. For example, a moth promoter for the cecropin B gene has been found to function appropriately in a mammalian cell.
摘要翻译： 已经发现了增加动物宿主（包括人类）对由细胞内细菌，原生动物和病毒引起的疾病的抵抗力的新方法。 所治疗的感染可能是例如马传染性贫血或人类免疫缺陷病毒的感染。 还发现了新的治疗肿瘤的方法。 通过用编码天然或合成裂解肽的外源基因“宿主”宿主的细胞来实现宿主对传染病或肿瘤防御的增强。 例如，造血干细胞和胚胎细胞的转染将产生具有增强的抗病性的动物; 并且转染TIL（肿瘤浸润淋巴细胞）细胞或其他细胞可用于治疗肿瘤。 编码天蚕素或其他天然或合成裂解肽的基因可以在哺乳动物，骨鱼，其他脊椎动物和其他动物细胞中转移并稳定表达。 转化的细胞具有产生和分泌广谱化学治疗剂的能力，该化学治疗剂对某些病原体尤其是可能逃避或克服宿主防御的病原体具有全身作用。 也已经发现了用对转录于对急性期肽或蛋白质的诱导物有响应的外源启动子控制的基因转化真核细胞的新方法。 例如，已经发现杀真菌素B基因的蛾启动子在哺乳动物细胞中适当地起作用。
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公开(公告)号：US07566777B2
公开(公告)日：2009-07-28
申请号：US10617561
申请日：2003-07-11
申请人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Kenneth L. Koonce , Samuel M. McCann , Wen H. Yu , Patricia A. Melrose , Lane D. Foil , Philip H. Elzer
发明人： Frederick M. Enright , Jesse M. Jaynes , William Hansel , Kenneth L. Koonce , Samuel M. McCann , Wen H. Yu , Patricia A. Melrose , Lane D. Foil , Philip H. Elzer
CPC分类号： C12N15/8257 , A61K38/00 , C07K7/23 , C07K14/43563 , C07K14/575 , C07K14/59 , C07K19/00 , C07K2319/00
摘要： Amphipathic lytic peptides are ideally suited to use in a ligand/cytotoxin combination to specifically inhibit cells that are driven by or are dependent upon a specific ligand interaction; for example, to induce sterility or long-term contraception, or to attack tumor cells, or to selectively lyse virally-infected cells, or to attack lymphocytes responsible for autoimmune diseases. The peptides act directly on cell membranes, and need not be internalized. Administering a combination of gonadotropin-releasing hormone (GnRH) (or a GnRH agonist) and a membrane-active lytic peptide produces long-term contraception or sterilization in animals in vivo. Administering in vivo a combination of a ligand and a membrane-active lytic peptide kills cells with a receptor for the ligand. The compounds are relatively small, and are not antigenic. Lysis of gonadotropes has been observed to be very rapid (on the order of ten minutes.) Lysis of tumor cells is rapid. The two components—the ligand and the lytic peptide—may optionally be administered as a fusion peptide, or they may be administered separately, with the ligand administered slightly before the lytic peptide, to activate cells with receptors for the ligand, and thereby make those cells susceptible to lysis by the lytic peptide. The compounds may be used in gene therapy to treat malignant or non-malignant tumors, and other diseases caused by clones or populations of “normal” host cells bearing specific receptors (such as lymphocytes), because genes encoding a lytic peptide or encoding a lytic peptide/peptide hormone fusion may readily be inserted into hematopoietic stem cells or myeloid precursor cells.
摘要翻译： 两亲性溶解肽理想地适用于配体/细胞毒素组合以特异性抑制由特定配体相互作用驱动或依赖于特定配体相互作用的细胞; 例如，诱导不育或长期避孕，或攻击肿瘤细胞，或选择性裂解病毒感染的细胞，或攻击负责自身免疫性疾病的淋巴细胞。 肽直接作用于细胞膜上，不需要内化。 管理促性腺激素释放激素（GnRH）（或GnRH激动剂）和膜活性溶解肽的组合在体内产生长期的动物避孕或灭菌。 在体内施用配体和膜活性裂解肽的组合将细胞与配体的受体杀死。 化合物相对较小，不具抗原性。 已经观察到促性腺激素的裂解非常快（十分钟左右）。肿瘤细胞裂解很快。 两种组分 - 配体和溶解肽 - 可以任选地作为融合肽施用，或者它们可以分开施用，配体在裂解肽之前略微施用，以激活配体受体的细胞，从而使得 易溶于裂解肽的细胞。 这些化合物可以用于治疗恶性或非恶性肿瘤的基因治疗，以及由具有特异性受体（如淋巴细胞）的“正常”宿主细胞的克隆或群体引起的其它疾病，因为编码溶解肽或编码溶酶体的基因 肽/肽激素融合可容易地插入到造血干细胞或骨髓前体细胞中。
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