Laboratory of Food Biotechnology, Post-Graduation Program in Biotechnology, University of Vale do Taquari-UNIVATES, Lajeado, RS, Brazil.
Cell Culture Laboratory, Post-Graduation Program in Biotechnology, University of Vale do Taquari-UNIVATES, Av. Avelino Tallini, 171, Lajeado, RS, 95914-014, Brazil.
Inflammopharmacology. 2019 Jun;27(3):433-452. doi: 10.1007/s10787-019-00589-2. Epub 2019 Mar 30.
While the inactivation mutations that eliminate JAK3 function lead to the immunological disorders such as severe combined immunodeficiency, activation mutations, causing constitutive JAK3 signaling, are known to trigger various types of cancer or are responsible for autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel diseases. Treatment of hyperactivated JAK3 is still an obstacle, due to different sensibility of mutation types to conventional drugs and unwanted side effects, because these drugs are not absolutely specific for JAK3, thus inhibiting other members of the JAK family, too. Lack of information, in which way sole inhibition of JAK3 is necessary for elimination of the disease, calls for the development of isoform-specific JAK3 inhibitors. Beside this strategy, up to date peptides are a rising alternative as chemo- or immunotherapeutics, but still sparsely represented in drug development and clinical trials. Beyond a possible direct inhibition function, crossing the cancer cell membrane and interfering in disease-causing pathways or triggering apoptosis, peptides could be used in future as adjunct remedies to potentialize traditional therapy and preserve non-affected cells. To discuss such feasible topics, this review deals with the knowledge about the structure-function of JAK3 and the actual state-of-the-art of isoform-specific inhibitor development, as well as the function of currently approved drugs or those currently being tested in clinical trials. Furthermore, several strategies for the application of peptide-based drugs for cancer therapy and the physicochemical and structural relations to peptide efficacy are discussed, and an overview of peptide sequences, which were qualified for clinical trials, is given.
虽然消除 JAK3 功能的失活突变会导致严重联合免疫缺陷等免疫紊乱，但导致组成性 JAK3 信号的激活突变已知会引发各种类型的癌症或导致自身免疫性疾病，如类风湿关节炎、银屑病或炎症性肠病。由于突变类型对常规药物的敏感性不同和不必要的副作用，治疗过度激活的 JAK3 仍然是一个障碍，因为这些药物并非绝对特异性针对 JAK3，因此也抑制了 JAK 家族的其他成员。由于缺乏关于单独抑制 JAK3 对消除疾病的必要性的信息，因此需要开发同工型特异性 JAK3 抑制剂。除了这种策略之外，截至目前，肽类是作为化学疗法或免疫疗法的新兴替代品，但在药物开发和临床试验中仍很少见。除了可能具有直接抑制功能外，肽类还可以穿过癌细胞膜，干扰致病途径或触发细胞凋亡，将来可以作为辅助疗法，增强传统疗法并保护未受影响的细胞。为了讨论这些可行的主题，本综述涉及 JAK3 的结构-功能以及同工型特异性抑制剂开发的最新进展，以及目前批准的药物或正在临床试验中测试的药物的功能。此外，还讨论了基于肽的药物在癌症治疗中的应用的几种策略以及与肽疗效的物理化学和结构关系，并概述了有资格进行临床试验的肽序列。
