RANDOM PEPTIDE DRUG DEVELOPMENT

随机肽药物开发

• 批准号: 6236375
• 负责人: SYDNEY E SALMON
• 金额: $ 18.14万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-15 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6236375
• 关键词: SCID mouse; drug design /synthesis /production; enzyme inhibitors; neoplasm /cancer invasiveness; nonHodgkin's lymphoma; peptide chemical synthesis; peptide library; phospholipase C; protein sequence

The central focus of project 29 is to develop growth-inhibitory peptides for the treatment of cancer using the random synthetic peptide library synthesis and testing technology ("Selective process") originally conceived of by this project's leaders. This new technology (which can use natural and/or unnatural amino acids) will be used to identify novel peptide ligands which bind with high affinity to 1 of 3 specific molecular targets: (1) cell-surface Ig in B-cell non-Hodgkin's lymphoma (NHL), (2) the enzyme matrilysin (MMP-7), implicated in tumor cell invasion, and (3) the enzyme phosphatidylinositol phospholipase C(PtdInsPLc, PLC), implicated in intracellular signalling after growth factor interaction with tumor cells. High affinity peptides binding to cell-surface Ig from human B-cell lymphomas will be tested for immunotherapeutic growth-inhibitory properties first in preclinical human lymphoma models in vitro and in SCID mice using either unlabeled or radioiodinated techniques. Success in these models will be lead to the subsequent clinical development of patient Cancer Center through project 19. Synthesis of specific random peptides which bind MMP-7 with high affinity and which also inhibit the function of this tumor-secreted enzyme will be scaled up for preclinical testing in vitro and in animal models for tumor cell invasion and for adjuvant therapy of cancer. Identification of specific random peptides which inhibit PLC enzyme activity will be followed with testing in cellular systems to determine whether the peptide leads can inhibit intracellular signalling after growth factor stimulation of tumor cells. Lead peptide inhibitors for PLC will also be tested in relevant human tumor models in SCID mice. Success in these enzyme-inhibition models will lead to selection of candidate peptides for formal pharmaceutical development via industrial collaborators. Phase I/II studies of successful enzyme inhibitors with antitumor activity in animal models would be conducted via project 19 after approval of IND's by the FDA.

项目29的中心焦点是开发生长抑制肽 用于使用随机合成肽文库治疗癌症 合成和测试技术（“选择性过程”）最初 是由这个项目的领导者构想出来的。 这项新技术（可以 使用天然和/或非天然氨基酸）将用于鉴定新的 肽配体以高亲和力结合3种特异性 分子靶点：（1）B细胞非霍奇金淋巴瘤的细胞表面IG (NHL)（2）基质溶解素（MMP-7），与肿瘤细胞 侵袭，和（3）磷脂酰肌醇磷脂酶 C（PtdInsPLc，PLC），参与生长后的细胞内信号传导 因子与肿瘤细胞的相互作用。 高亲和力肽结合 将检测来自人B细胞淋巴瘤的细胞表面IG， 免疫细胞生长抑制特性首次应用于临床前人类 使用未标记的或未标记的细胞在体外和SCID小鼠中的淋巴瘤模型， 放射性碘标记技术。 这些模式的成功将导致 病人癌症中心后续临床发展通过项目 19. MMP-7特异性高亲和力结合肽的合成 亲和性，并抑制这种肿瘤分泌的功能， 酶将按比例放大，用于体外和动物临床前试验 用于肿瘤细胞侵袭和癌症辅助治疗的模型。 PLC酶特异性抑制随机肽的鉴定 活动之后将在蜂窝系统中进行测试，以确定 肽前导是否可以抑制细胞内信号传导， 肿瘤细胞的生长因子刺激。 先导肽抑制剂， PLC还将在SCID小鼠的相关人类肿瘤模型中进行测试。 这些酶抑制模型的成功将导致选择 用于通过工业化进行正式药物开发的候选肽 合作者 成功的酶抑制剂的I/II期研究 动物模型中的抗肿瘤活性将通过项目19进行 在FDA批准IND之后。