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公开(公告)号：US20050256040A1
公开(公告)日：2005-11-17
申请号：US10846479
申请日：2004-05-14
申请人： Dale Bredesen , H. Michael Ellerby
发明人： Dale Bredesen , H. Michael Ellerby
IPC分类号： A61K38/17
CPC分类号： A61K38/17
摘要： Protein engineering is an emerging area that has expanded the understanding in the art of protein folding and laid the groundwork for the creation of unprecedented structures with unique functions. The first native-like pore-forming protein, small globular protein (SGP), has previously been designed. It has now been discovered that this artificially engineered protein, and analogs and homologs thereof, have membrane-disrupting properties and anti-tumor activity in several cancer animal models. A mechanism for the selectivity of SGP toward cell membranes in tumors is proposed and validated herein, thereby confirming the proposed mechanism of action. Thus, SGP is established herein as the prototype for a new class of artificial proteins designed for therapeutic applications.
摘要翻译： 蛋白质工程是一个新兴领域，扩大了蛋白质折叠技术的理解，为创造具有独特功能的前所未有的结构奠定了基础。 先前设计了第一种天然样成孔蛋白，小球状蛋白（SGB）。 现在已经发现，这种人工设计的蛋白质及其类似物和同系物在几种癌症动物模型中具有膜破坏性质和抗肿瘤活性。 本文提出并验证了SGP对肿瘤细胞膜选择性的机制，从而证实了所提出的作用机制。 因此，本文建立SGP作为为治疗应用设计的新类型人造蛋白的原型。
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公开(公告)号：US20080188421A1
公开(公告)日：2008-08-07
申请号：US11795703
申请日：2005-03-31
申请人： Dale E. Bredesen , Michael Ellerby , Lisa Ellerby
发明人： Dale E. Bredesen , Michael Ellerby , Lisa Ellerby
摘要： The present invention provides homing conjugates containing an antimicrobial peptide and a tumor homing molecule, wherein the tumor homing molecule comprises a dimer of two endothelium-homing peptide monomers, wherein the conjugate homes to and is internalized by a tumor cell type or tissue comprising angiogenic endothelial cells and exhibits high toxicity thereto, wherein the high toxicity is due to disruption of mitochondrial membranes, and wherein the antimicrobial peptide has low mammalian cell toxicity when not linked to said tumor homing molecule. The present invention is based, in part, on the discovery that dimerization of endothelium-homing peptide monomer confers greatly increased cytotoxic activity on the conjugate. Based on this discovery, the invention further provides methods of inducing selective toxicity in vivo in an angiogenic endothelial tissue or cell type as well as methods of treating an individual having cancer by administering an effective amount of a homing conjugate of the invention also are provided.
摘要翻译： 本发明提供了含有抗微生物肽和肿瘤归巢分子的归巢缀合物，其中所述肿瘤归巢分子包含两个内皮归巢肽单体的二聚体，其中所述缀合物归因于包含血管生成内皮的肿瘤细胞类型或组织 细胞并且对其呈现高毒性，其中高毒性是由于线粒体膜的破坏，并且其中当不与所述肿瘤归巢分子连接时，所述抗微生物肽具有低的哺乳动物细胞毒性。 本发明部分地基于发现内皮归巢肽单体的二聚化大大提高了缀合物的细胞毒活性。 基于该发现，本发明还提供了在血管生成内皮组织或细胞类型中诱导体内选择性毒性的方法以及通过施用有效量的本发明的归巢缀合物治疗患有癌症的个体的方法。
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