Peterson L B, Cryan J G, Rosa R, Martin M M, Wilusz M B, Sinclair P J, Wong F, Parsons J N, O'Keefe S J, Parsons W H, Wyvratt M, Sigal N H, Williamson A R, Wiederrecht G J
Department of Molecular Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Transplantation. 1998 Jan 15;65(1):10-8. doi: 10.1097/00007890-199801150-00004.
Tacrolimus (FK506) is an immunosuppressive drug 50-100 times more potent than cyclosporine (CsA), the current mainstay of organ transplant rejection therapy. Despite being chemically unrelated, CsA and tacrolimus exert their immunosuppressive effects through the inhibition of calcineurin (CaN), a critical signaling molecule during T-lymphocyte activation. Although numerous clinical studies have proven the therapeutic efficacy of drugs within this class, tacrolimus and CsA also have a strikingly similar profile of unwanted side effects.
Our objective has been to identify a less toxic immunosuppressant through the modification of ascomycin (FK520). Quantitative in vitro immunosuppression and toxicity assays have demonstrated (see the accompanying article, p. 18) that we achieved our goal with L-732,531 (indolyl-ascomycin; indolyl-ASC), a 32-O-(1-hydroxyethylindol-5-yl) ascomycin derivative with an improved therapeutic index relative to tacrolimus.
We report that the attributes of indolyl-ASC may result from its distinctive biochemical properties. In contrast to tacrolimus, indolyl-ASC binds poorly to FK506 binding protein 12 (FKBP12), the major cytosolic receptor for tacrolimus and related compounds. However, the stability of the interaction between the FKBP12-indolyl-ASC complex and CaN is much greater than that of the FKBP12-tacrolimus complex. These distinguishing properties of indolyl-ASC result in the potent inhibition of CaN within T lymphocytes but may lower the accumulation of the drug at sites of toxicity.
Indolyl-ASC may define those properties needed to increase the therapeutic efficacy of a macrolactam immunoregulant for treating both human autoimmune disease and organ transplant rejection.
他克莫司（FK506）是一种免疫抑制药物，其效力比目前器官移植排斥反应治疗的主要药物环孢素（CsA）强50至100倍。尽管化学结构无关，但CsA和他克莫司通过抑制钙调神经磷酸酶（CaN）发挥免疫抑制作用，CaN是T淋巴细胞激活过程中的关键信号分子。虽然众多临床研究已证实此类药物的治疗效果，但他克莫司和CsA也具有极为相似的不良副作用。
我们的目标是通过对阿索霉素（FK520）进行修饰来鉴定一种毒性较小的免疫抑制剂。定量体外免疫抑制和毒性试验表明（见随附文章，第18页），我们用L - 732,531（吲哚基 - 阿索霉素；吲哚基 - ASC）实现了目标，L - 732,531是一种32 - O -（1 - 羟乙基吲哚 - 5 - 基）阿索霉素衍生物，其治疗指数相对于他克莫司有所提高。
我们报告吲哚基 - ASC的特性可能源于其独特的生化特性。与他克莫司不同，吲哚基 - ASC与FK506结合蛋白12（FKBP12）的结合能力较差，FKBP12是他克莫司及相关化合物的主要胞质受体。然而，FKBP12 - 吲哚基 - ASC复合物与CaN之间相互作用的稳定性远大于FKBP12 - 他克莫司复合物。吲哚基 - ASC的这些独特特性导致其对T淋巴细胞内的CaN有强力抑制作用，但可能会降低药物在毒性部位的蓄积。
吲哚基 - ASC可能确定了提高大环内酯类免疫调节剂治疗人类自身免疫性疾病和器官移植排斥反应疗效所需的特性。
