Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors.
Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors.
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DOI：
10.1016/j.chembiol.2016.07.022
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发表时间：
2016-09-22
影响因子：
8.6
通讯作者：
Walensky LD
中科院分区：
文献类型：
--
作者：
Huhn AJ;Guerra RM;Harvey EP;Bird GH;Walensky LD
抗凋亡bcl2家族蛋白通过在表面沟槽中捕获促凋亡成员的关键α-螺旋BH3结构域来阻止细胞死亡。癌细胞通过过度表达一系列抗凋亡分子来劫持这种生存机制，从而建立起强大的凋亡阻滞剂来抵制化疗。选择性bcl2抑制剂ABT-199在重新激活依赖bcl2的癌症中的凋亡方面取得了临床成功，这推动了对BH3结合的抗凋亡蛋白片段的药物治疗成为一个最优先的目标。BFL-1是一种BCL-2同系物，与黑色素瘤、淋巴瘤和其他癌症有关，目前仍未被下药。NOXA BH3螺旋和BFL-1口袋结合界面上两个独特的半胱氨酸的自然并列导致了含有丙烯酰胺弹头的BH3多肽的发展，通过共价靶向不可逆转地抑制BFL-1。鉴于天然半胱氨酸经常接近调节结合表面，共价结合多肽抑制剂为靶向病理性蛋白相互作用提供了一种新的治疗策略。Huhn et al.报道了在抗细胞凋亡的BFL-1的BH3结合界面上与离散半胱氨酸发生共价反应的装订多肽的发展，代表了在癌症和其他疾病中选择性共价靶向病理蛋白的新策略。
Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical α-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2 dependent cancers. BFL-1 is a BCL-2 homologue implicated in melanoma, lymphoma, and other cancers, and remains undrugged. A natural juxtaposition of two unique cysteines at the binding interface of the NOXA BH3 helix and BFL-1 pocket informed the development of stapled BH3 peptides bearing acrylamide warheads to irreversibly inhibit BFL-1 by covalent targeting. Given the frequent proximity of native cysteines to regulatory binding surfaces, covalent stapled peptide inhibitors provide a new therapeutic strategy for targeting pathologic protein interactions. Huhn et al. report the development of stapled peptides that covalently react with a discrete cysteine at the BH3-binding interface of anti-apoptotic BFL-1, representing a new strategy for selective covalent targeting of pathologic proteins in cancer and other diseases.
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影响因子：
64.8
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影响因子：
9
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64.5
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作者：
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通讯作者：
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51.1
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