SUBSTRATES FOR PEPTIDYL PROLYL CIS-TRANS ISOMERASE ASSAY

描述：(改编自申请人的摘要)最近的报告有 提示新型高效免疫抑制剂FK-506是一种 预防人体器官移植排斥反应的有效药物 显示出与环孢素A(CsA)不同的毒性特征。一位少校 被FKBP抑制的FK-506结合蛋白被证明是一种 肽基-脯氨酰顺式-反式异构酶，由 FK-506。丙酰基异构化活性也显示出主要的 环孢素A结合蛋白，亲环素，被特异性抑制 由CSA提供。这种异构化现象的研究及其在石油化工中的开发 开发治疗自身免疫性疾病的新型免疫抑制剂 器官移植排斥反应也因技术困难而受阻。 在异构化实验中。这项研究的近期目标描述 在这一阶段，拨款申请是要制定具体的、敏感的 多肽基-卟啉顺反异构酶的底物研究 活动。较长期的计划包括应用对 异构酶-底物的相互作用从而获得了特异性的发展 这些酶的抑制剂。通过这种方式，调查人员计划 解决Pro异构化催化作用是否具有因果关系的问题 因为免疫抑制或仅仅是一种不确定的现象，可能 有助于这些化合物的毒性，并应用这一知识 对未来几代免疫调节药物的开发。

DESCRIPTION: (Adapted from the applicant's abstract) Recent reports have indicated that FK-506, a novel, highly potent immunosuppressant, is an effective agent for preventing organ transplant rejection in man which displays a different toxicity profile than cyclosporin A (CsA). A major FK-506 binding protein, inhibited by FKBP, has been shown to be a peptidyl-prolyl cis-trans isomerase that is specifically inhibited by FK-506. Prolyl isomerization activity is also displayed by the main cyclosporin A binding protein, cyclophilin, which is specifically inhibited by CsA. The study of this isomerization phenomenon and its exploitation to develop novel immunosuppressants for the treatment of autoimmune disease and organ transplant rejection has been hampered by technical difficulties in the isomerization assay. The immediate goal of the research described in this Phase I grant application is to develop specific, sensitive substrates for the assessment of peptidyl-porlyl cis-trans isomerase activity. Longer-range plans involve applying the understanding of isomerase-substrate interactions thus gained to the development of specific inhibitors of these enzymes. In this manner, the investigators plan to address the issue of whether catalysis of prolyl isomerization is causal for immunosuppression or is merely an adventitious phenomenon, possibly contributing to the toxicity of these compounds and to apply this knowledge to the development of future generations of immunomodulatory drugs.