公开(公告)号：US20070224212A1

公开(公告)日：2007-09-27

申请号：US11628483

申请日：2005-05-27

申请人： Elisabetta Bianchi ,  Antonello Pessi ,  Romas Geleziunas ,  David Bramhill

发明人： Elisabetta Bianchi ,  Antonello Pessi ,  Romas Geleziunas ,  David Bramhill

IPC分类号： C12Q1/70

CPC分类号： C07K14/005 ,  A61K38/00 ,  A61K39/00 ,  A61K39/12 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134 ,  G01N2333/16 ,  G01N2500/02

摘要： Methods of covalently-stabilizing alpha-helical, chimeric peptides constrained within a homotrimeric or heterotrimeric coiled-coil structure are disclosed. The coiled-coil structures made by the methods disclosed within this specification mimic all or a portion of the internal, trimeric coiled-coil motif contained within the fusogenic conformation of an enveloped virus membrane-fusion protein, particularly the internal coiled-coil domain of the HIV gp41 ectodomain. The HIV-derived, chimeric peptides disclosed comprise a non-HIV, soluble, trimeric form of a coiled-coil fused in helical phase to all or a portion of the N-helix of HIV gp41 and are covalently-stabilized in a homotrimeric or heterotrimeric coiled-coil structure through the formation of disulfide or chemoselective bonds between said peptides. The covalently-stabilized, HIV-derived, homotrimeric or heterotrimeric coiled-coil structures made by the methods disclosed herein represent a close mimetic of a HIV gp41 fusion intermediate and are potent inhibitors of HIV infectivity. These HIV-derived chimeric peptides may provide for therapeutic treatment against HIV infection by inhibiting the virus-host cell membrane fusion process.

摘要翻译： 公开了限制在同三聚体或异三聚体卷曲螺旋结构内的共价稳定的α-螺旋嵌合肽的方法。 通过本说明书中公开的方法制备的盘绕线圈结构模拟包含在包膜病毒膜 - 融合蛋白的融合构象内的内部三聚体卷曲螺旋基序的全部或一部分，特别是内部卷曲螺旋结构域 HIV gp41胞外域。 所公开的HIV衍生的嵌合肽包含螺旋状螺旋状的非HIV，可溶性三聚体形式，其与HIV gp41的全部或部分N-螺旋融合，并且以同三聚或异三聚体共价稳定 通过在所述肽之间形成二硫键或化学选择性键来进行卷曲螺旋结构。 由本文公开的方法制备的共价稳定的HIV衍生的同源三聚体或异三聚体卷曲螺旋结构代表HIV gp41融合中间体的密切模拟物，并且是HIV感染性的有效抑制剂。 这些HIV衍生的嵌合肽可以通过抑制病毒宿主细胞膜融合过程来提供针对HIV感染的治疗性治疗。

公开(公告)号：US07811577B2

公开(公告)日：2010-10-12

申请号：US11628483

申请日：2005-05-27

申请人： Elisabetta Bianchi ,  Antonello Pessi ,  Romas Geleziunas ,  David Bramhill

发明人： Elisabetta Bianchi ,  Antonello Pessi ,  Romas Geleziunas ,  David Bramhill

IPC分类号： A61K39/00 ,  A61K39/21

CPC分类号： C07K14/005 ,  A61K38/00 ,  A61K39/00 ,  A61K39/12 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134 ,  G01N2333/16 ,  G01N2500/02

摘要： Methods of covalently-stabilizing alpha-helical, chimeric peptides constrained within a homotrimeric or heterotrimeric coiled-coil structure are disclosed. The coiled-coil structures made by the methods disclosed within this specification mimic all or a portion of the internal, trimeric coiled-coil motif contained within the fusogenic conformation of an enveloped virus membrane-fusion protein, particularly the internal coiled-coil domain of the HIV gp41 ectodomain. The HIV-derived, chimeric peptides disclosed comprise a non-HIV, soluble, trimeric form of a coiled-coil fused in helical phase to all or a portion of the N-helix of HIV gp41 and are covalently-stabilized in a homotrimeric or heterotrimeric coiled-coil structure through the formation of disulfide or chemoselective bonds between said peptides. The covalently-stabilized, HIV-derived, homotrimeric or heterotrimeric coiled-coil structures made by the methods disclosed herein represent a close mimetic of a HIV gp41 fusion intermediate and are potent inhibitors of HIV infectivity. These HIV-derived chimeric peptides may provide for therapeutic treatment against HIV infection by inhibiting the virus-host cell membrane fusion process.

摘要翻译： 公开了限制在同三聚体或异三聚体卷曲螺旋结构内的共价稳定的α-螺旋嵌合肽的方法。 通过本说明书中公开的方法制备的盘绕线圈结构模拟包含在包膜病毒膜 - 融合蛋白的融合构象内的内部三聚体卷曲螺旋基序的全部或一部分，特别是内部卷曲螺旋结构域 HIV gp41胞外域。 所公开的HIV衍生的嵌合肽包含螺旋状螺旋状的非HIV，可溶性三聚体形式，其与HIV gp41的全部或部分N-螺旋融合，并以共三聚体或异三聚体共价稳定 通过在所述肽之间形成二硫键或化学选择性键来进行卷曲螺旋结构。 由本文公开的方法制备的共价稳定的HIV衍生的同源三聚体或异三聚体卷曲螺旋结构代表HIV gp41融合中间体的密切模拟物，并且是HIV感染性的有效抑制剂。 这些HIV衍生的嵌合肽可以通过抑制病毒宿主细胞膜融合过程来提供针对HIV感染的治疗性治疗。

公开(公告)号：US07744887B2

公开(公告)日：2010-06-29

申请号：US11628164

申请日：2005-05-31

申请人： John W. Shiver ,  Michael D. Miller ,  Romas Geleziunas ,  Daria J. Hazuda ,  Peter S. Kim ,  Debra M. Eckert ,  Michael J. Root ,  Simon N. Lennard ,  Elisabetta Bianchi

发明人： John W. Shiver ,  Michael D. Miller ,  Romas Geleziunas ,  Daria J. Hazuda ,  Peter S. Kim ,  Debra M. Eckert ,  Michael J. Root ,  Simon N. Lennard ,  Elisabetta Bianchi

IPC分类号： A61K39/42 ,  G01N33/53 ,  A61K39/395 ,  C12P16/00

CPC分类号： G01N33/56988 ,  C07K16/1063 ,  C07K2317/21 ,  C07K2317/622 ,  C07K2317/76 ,  G01N2500/00

摘要： Human scFvs are disclosed which interact with a conformational epitope along the pre-hairpin, N-helix coiled coil structure within the heptad repeat 1 (HR1) region of gp41 of HIV. These antibodies, as well as IgG conversions, are shown to neutralize diverse HIV isolates. Isolated nucleic acid molecules are also disclosed which encode relevant portions of these antibodies, as well as the purified forms of the expressed antibodies or relevant antibody fragments, such as VH and VL chains. The antibody compositions disclosed within this specification may provide for a therapeutic treatment against HIV infection by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV infection. These antibodies will also be useful in assays to identify HIV antiviral compounds as well as allowing for the identification of candidate HIV vaccines, such as HIV peptide vaccines.

摘要翻译： 披露了人scFv，其与艾滋病病毒gp41的七重复重复1（HR1）区域内的前发夹，N-螺旋卷曲螺旋结构与构象表位相互作用。 显示出这些抗体以及IgG转化中和多种HIV分离物。 还公开了分离的核酸分子，其编码这些抗体的相关部分，以及所表达的抗体或相关抗体片段（例如VH和VL链）的纯化形式。 在本说明书中公开的抗体组合物可通过降低受感染个体内的病毒载量水平来提供抗HIV感染的治疗性治疗，从而延长HIV感染的无症状期。 这些抗体也可用于鉴定HIV抗病毒化合物的测定，以及允许鉴定候选的HIV疫苗，例如HIV肽疫苗。

公开(公告)号：US20070248613A1

公开(公告)日：2007-10-25

申请号：US11628164

申请日：2005-05-31

申请人： John Shiver ,  Michael Miller ,  Romas Geleziunas ,  Daria Hazuda ,  Peter Kim ,  Debra Eckert ,  Michael Root ,  Simon Lennard ,  Elisabetta Bianchi

发明人： John Shiver ,  Michael Miller ,  Romas Geleziunas ,  Daria Hazuda ,  Peter Kim ,  Debra Eckert ,  Michael Root ,  Simon Lennard ,  Elisabetta Bianchi

IPC分类号： A61K39/395 ,  A61K33/00 ,  A61P31/18 ,  C07H21/04 ,  C07K16/00 ,  C12N15/00 ,  C12P21/06 ,  G01N33/566

CPC分类号： G01N33/56988 ,  C07K16/1063 ,  C07K2317/21 ,  C07K2317/622 ,  C07K2317/76 ,  G01N2500/00

摘要： Human scFvs are disclosed which interact with a conformational epitope along the pre-hairpin, N-helix coiled coil structure within the heptad repeat 1 (HR1) region of gp41 of HIV. These antibodies, as well as IgG conversions, are shown to neutralize diverse HIV isolates. Isolated nucleic acid molecules are also disclosed which encode relevant portions of these antibodies, as well as the purified forms of the expressed antibodies or relevant antibody fragments, such as VH and VL chains. The antibody compositions disclosed within this specification may provide for a therapeutic treatment against HIV infection by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV infection. These antibodies will also be useful in assays to identify HIV antiviral compounds as well as allowing for the identification of candidate HIV vaccines, such as HIV peptide vaccines.

摘要翻译： 披露了人scFv，其与艾滋病病毒gp41的七重复重复1（HR1）区域内的前发夹，N-螺旋卷曲螺旋结构与构象表位相互作用。 显示出这些抗体以及IgG转化中和多种HIV分离物。 还公开了分离的核酸分子，其编码这些抗体的相关部分，以及所表达的抗体或相关抗体片段的纯化形式，例如V H H和V L >链。 在本说明书中公开的抗体组合物可通过降低受感染个体内的病毒载量水平来提供抗HIV感染的治疗性治疗，从而延长HIV感染的无症状期。 这些抗体也可用于鉴定HIV抗病毒化合物的测定，以及允许鉴定候选的HIV疫苗，例如HIV肽疫苗。