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    Anti-fibril peptides
    5.
    发明授权
    Anti-fibril peptides 有权
    抗原纤维肽

    公开(公告)号：US07345022B2

    公开(公告)日：2008-03-18

    申请号：US10666095

    申请日：2003-09-18

    申请人： Robert P. Hammer ,  Yanwen Fu ,  Tod J. Miller ,  Mark L. McLaughlin

    发明人： Robert P. Hammer ,  Yanwen Fu ,  Tod J. Miller ,  Mark L. McLaughlin

    IPC分类号： A61K38/03 ,  A61K38/08 ,  A61K38/10 ,  C07K4/00 ,  C07K7/06 ,  C07K7/08

    CPC分类号： C07K7/06 ,  A61K38/00 ,  C07K5/0806 ,  C07K5/1008 ,  C07K5/1019 ,  C07K7/08 ,  C07K14/4711

    摘要： Novel peptides are disclosed that may be used as inhibitors of amyloidogenesis, as suppressors of amyloid toxicity, and as therapeutic agents for amyloid-associated diseases such as Alzheimer's disease, Parkinson's Disease, Creutzfeldt-Jakob Disease, Huntington's Disease, and Type II Diabetes. These new β-strand mimics (β-sheet “blockers”), containing Cα,α-disubstituted amino acids, specifically interact with and block the development of the β-sheet structure of the developing fibrils of amyloid diseases, such as Alzheimer's disease amyloid β-peptide (Aβ). We have discovered that oligomerization of β-sheet structures, including those implicated in amyloid-associated diseases, may be inhibited or even reversed by the presence of extended peptide structures that have only one edge available for hydrogen bonding. Without a second edge that is also available for hydrogen bonding, the extension of a developing β-sheet is blocked by binding to the novel peptides.

    摘要翻译： 公开了可用作淀粉样蛋白发生抑制剂的新型肽，作为淀粉样蛋白毒性的抑制剂，以及作为淀粉样蛋白相关疾病如阿尔茨海默氏病，帕金森氏病，克雅氏病，亨廷顿氏病和II型糖尿病的治疗剂。 这些新的β链模拟物（β-片段“阻断剂”），含有Cα，α - 二取代的氨基酸，特异性地相互作用并阻断了发展中的原纤维的β-折叠结构 淀粉样蛋白疾病，如阿尔茨海默病淀粉样蛋白β-肽（Abeta）。 我们已经发现，β-片结构的低聚，包括涉及淀粉样蛋白相关疾病的那些，可能被抑制或甚至被仅具有一个可用于氢键的边缘的延伸肽结构的存在所逆转。 没有可用于氢键的第二边缘，通过与新肽的结合阻断了显影的β-折叠片的延伸。

    Anti-fibril peptides
    6.
    发明申请
    Anti-fibril peptides 有权

    公开(公告)号：US20050119187A1

    公开(公告)日：2005-06-02

    申请号：US10666095

    申请日：2003-09-18

    申请人： Robert Hammer ,  Yanwen Fu ,  Jed Aucoin ,  Tod Miller ,  Mark McLaughlin ,  Robin McCarley

    发明人： Robert Hammer ,  Yanwen Fu ,  Jed Aucoin ,  Tod Miller ,  Mark McLaughlin ,  Robin McCarley

    IPC分类号： A61K38/00 ,  C07K5/083 ,  C07K5/103 ,  C07K5/11 ,  C07K7/06 ,  C07K7/08 ,  C07K14/47 ,  A61K38/08

    CPC分类号： C07K7/06 ,  A61K38/00 ,  C07K5/0806 ,  C07K5/1008 ,  C07K5/1019 ,  C07K7/08 ,  C07K14/4711

    摘要： Short peptides containing Cα,α-dipropylglycine (Dpg) at alternating sequence positions were synthesized and examined for conformational behavior. Peptide assembly was performed using Fmoc-solid-phase chemistry where the coupling with PyAOP could be significantly enhanced at elevated temperature. Circular dichroism (CD) and NMR conformational studies revealed that incorporation of Dpg residues induced folded structures into peptides. It was observed that Dpg residues adopted helical conformation in a helix-promoting sequence. The resulting helical structure was comprised of consecutive β-turns whose structure was stabilized by salt bridge in aqueous solution. In this study, the preparation of sterically and polyfunctional Cα,α-disubstituted amino acids (ααAAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gave the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic or hydrogen over Raney Ni gave the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The synthesis of a sterically demanding Cα,α-dibenzylglycine (Dbzg), and an orthogonally protected, tetrafunctional Cα,α-disubstituted analogue of aspartic acid Bcmg is described. The preparation of amyloid fibril blocker peptides based on amyloid peptide hydrophobic core Aβ16-20 is described. These blocker peptides containing sterically

    ANTI-CANCER PHOSPHOROTHIOATE-COUPLED PEPTIDE CONJUGATES AND METHODS OF USING THE SAME
    8.
    发明申请
    ANTI-CANCER PHOSPHOROTHIOATE-COUPLED PEPTIDE CONJUGATES AND METHODS OF USING THE SAME 有权

    公开(公告)号：US20210154305A1

    公开(公告)日：2021-05-27

    申请号：US16630347

    申请日：2018-07-13

    申请人： Yanwen FU ,  CITY OF HOPE

    发明人： Andreas HERRMANN ,  Hua YU ,  Yanwen FU

    IPC分类号： A61K47/54 ,  A61P35/00

    摘要： Provided herein are, inter alia, nucleic acid-peptide conjugates including a non-cell penetrating protein (e.g., an Hdm2 targeting peptide) attached at its C-terminus to a phosphorothioate nucleic acid. Attachment of the phosphorothioate nucleic acid to the non-cell penetrating protein conveys stability to and allows for efficient intracellular delivery of the non-cell penetrating peptide. The nucleic acid-peptide conjugates provided herein including embodiments thereof are useful, inter alia, for the treatment of cancer.