State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):E5986-E5994. doi: 10.1073/pnas.1706778114. Epub 2017 Jul 3.
Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.
肌苷单磷酸脱氢酶（IMPDH）是人免疫抑制剂的一个有吸引力的靶标。目前，小分子抑制剂对不同的 IMPDH 同工酶（IMPDH1 和 IMPDH2）没有很好的选择性，导致一些不良反应，限制了它们的应用。在此，我们使用一种专门针对 IMPDH2 的小分子探针，并确定半胱氨酸残基 140（Cys140）为一个选择性可药物化位点。通过与 Cys140 共价结合，该探针发挥别构调节作用，阻断 IMPDH2 的催化口袋，进一步诱导 IMPDH2 失活，从而有效抑制神经炎症反应。然而，该探针不会与 IMPDH1 发生共价结合。综上所述，我们的研究表明 Cys140 是选择性抑制 IMPDH2 的可药物化位点，为开发自身免疫和神经炎症疾病的治疗药物提供了巨大的潜力，具有更少的不良耐受性特征。
