Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A
Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A
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DOI：
10.1126/science.285.5436.2129
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发表时间：
1999-09-24
期刊：
影响因子：
56.9
通讯作者：
Rao, A
中科院分区：
文献类型：
--
作者：
Aramburu, J;Yaffe, MB;Rao, A
从钙动员受体到活化T细胞核因子（NFAT）依赖性基因的信息流严重依赖于磷酸酶钙调神经磷酸酶和转录因子NFAT之间的相互作用。基于NFAT的钙调神经磷酸酶对接基序，从组合肽库中选择高亲和力的钙调神经磷酸酶结合肽，该肽有效地抑制T细胞中NFAT活化和NFAT依赖性内源性细胞因子基因的表达，而不影响需要钙调神经磷酸酶而不是NFAT的其他细胞因子的表达。将优化的肽序列置换到天然钙调磷酸酶对接位点中增加了NFAT的钙调磷酸酶响应性。选择性干扰钙调磷酸酶-NFAT相互作用而不影响钙调磷酸酶磷酸酶活性的化合物可用作毒性低于现有药物的治疗剂。
The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide Libraries based on the calcineurin docking motif of NFAT, This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are Less toxic than current drugs.