Algorithmic Peptides Target Multidrug Resistance Protein

算法肽靶向多药耐药蛋白

• 批准号: 6668600
• 负责人: ARNOLD Joseph MANDELL
• 金额: $ 10万
• 依托单位: CIELO INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668600
• 关键词: P glycoprotein; antineoplastics; cell line; computer assisted sequence analysis; conformation; drug design /synthesis /production; ligands; mathematical model; membrane transport proteins; multidrug resistance; peptide library; protein engineering

DESCRIPTION (provided by applicant): One mechanism of emergent anticancer multidrug resistance is the induction of an ATP-dependent, membrane transport system, P-glycoprotein, P-gp, a pump which effluxes anticancer agents. We offer a peptide ligand design scheme as an agent source alternative to currently prominent empirically discovered small molecule inhibitors of substrate and/or nucleotide binding which often fail because they themselves are subject to and/or induce the P-gp pump in tumor cells. Our new scheme for computational hierarchical hydrophobic mode analysis and membrane protein mode matched peptide design target membrane protein extracellular loops and induce conformational transitions manifested by either positive or negative allosteric changes in their responses to their natural ligands and with approximately 30-50% hit rates. The cooperative conformational motions of P-gp?s nearly symmetric halves required for normal function make this approach different from and perhaps more promising than the more common binding-site targeted, small molecule inhibitors. Work since the previous submission suggest that these receptor hydrophobic mode matched algorithmic peptides, reversed in sequence and expressed in D amino acids, retro-inverso forms, less likely to be subject to the action and induction of the P-gp pump as well as the actions of peptidases (thus more easily deliverable, even orally), have similar effects in magnitude and direction as their ortho congeners. Hydrophobic mode-matched, algorithmically designed, conformationally active allosteric ortho and retro-inverso peptide agents will be tested against cancer drug transport and ATP utilization in spheroblasts, right sided vesicles and whole cell prokaryote systems expressing human P-gp. Ligand mode specificity will be addressed using 50 peptides generated from randomized eigenvector templates. The non-multidrug ATP-dependent transporter MDR3 will serve as a control for target specificity. Evidence that the anticipated 30% (75) or more of the 250 normal vector generated candidate algorithmic peptides will down regulate, impair or abrogate transport by this Phase I study using this in vitro simple cell system will encourage a Phase I submission for expanded peptide design and testing in P-gp expressing in vitro and in vivo mammalian cells systems as well as drug resistant human tumor cell lines.

描述（由申请人提供）： 出现的抗癌多药电阻的一种机制是诱导 依赖ATP的膜运输系统，P-糖蛋白，P-gp，泵 这会消失抗癌剂。我们提供肽配体设计方案 代理来源的替代方案，是当前突出的经验发现的 底物和/或核苷酸结合的小分子抑制剂，通常 失败是因为它们本身会受到和/或诱导P-gp泵 肿瘤细胞。我们的新计算分层疏水模式方案 分析和膜蛋白模式匹配肽设计目标膜 蛋白质外回路并诱导表现出构象转变 通过积极或负面的变构的反应变化 天然配体，命中率约为30-50％。合作社 p-gp？s的构象运动几乎是正常所需的对称的一半 功能使这种方法与 更常见的结合位点靶向小分子抑制剂。自从工作以来 以前的提交表明这些受体疏水模式匹配 算法肽，依次反转并在D氨基酸中表达， 复古的形式，不太可能受到行动和诱导的影响 P-gp泵以及肽酶的作用（因此更容易 可交付的甚至口头）在大小和方向上具有相似的影响 他们的矫正物。疏水模式匹配，算法设计， 构象活性的变构矫正型和恢复肽剂将 在spheroblasts中针对癌症药物运输和ATP利用进行测试， 右侧囊泡和表达人类P-gp的全细胞原核系统。 配体模式特异性将使用从随机特征向量模板产生的50个肽来解决。非Multidrug ATP依赖性转运蛋白 MDR3将作为目标特异性的控制。证据表明 预计250个正常矢量生成的候选者中有30％（75）或更多 算法肽将减少调节，损害或消除运输 使用此体外简单细胞系统的I期研究将鼓励I期 提交在体外表达P-gp中扩展的肽设计和测试 和体内哺乳动物细胞系统以及耐药的人肿瘤细胞 线。