Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets.
Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets.
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DOI：
10.1038/s41467-017-02098-8
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发表时间：
2017-12-21
影响因子：
16.6
通讯作者：
Olson JM
中科院分区：
文献类型：
--
作者：
Crook ZR;Sevilla GP;Friend D;Brusniak MY;Bandaranayake AD;Clarke M;Gewe M;Mhyre AJ;Baker D;Strong RK;Bradley P;Olson JM
蛋白质：蛋白质相互作用是最难处理的疾病病理分子机制之一。致密的半胱氨酸多肽有可能破坏这种相互作用，并被生命的每一个分支用作类似药物的角色，但由于其复杂的二硫键连接，它们的研究一直受到难以生产的名声的阻碍。在这里，我们描述了一个利用哺乳动物表面展示来鉴定靶结合的胱氨酸致密多肽的平台，该平台能够以可验证的折叠和稳定性来查询高质量和多样化的支架文库。我们通过鉴定一种能够抑制致癌河马途径核心的YAP：TEAD相互作用的胱氨酸致密多肽，并具有考虑作为药物开发候选所需的效力和稳定性来展示该平台的能力。这一平台提供了筛选具有药物性质的致密半胱氨酸多肽的机会，以对抗与疾病治疗有关但不适合传统方法的靶点。与蛋白质相关的病理：蛋白质相互作用很难治疗，但致密的半胱氨酸多肽有可能破坏这种相互作用。在这里，作者开发了一种高度多样性的哺乳动物细胞筛选具有药物潜力的胱氨酸致密多肽，并用它来鉴定YAP：TEAD抑制剂。
Protein:protein interactions are among the most difficult to treat molecular mechanisms of disease pathology. Cystine-dense peptides have the potential to disrupt such interactions, and are used in drug-like roles by every clade of life, but their study has been hampered by a reputation for being difficult to produce, owing to their complex disulfide connectivity. Here we describe a platform for identifying target-binding cystine-dense peptides using mammalian surface display, capable of interrogating high quality and diverse scaffold libraries with verifiable folding and stability. We demonstrate the platform’s capabilities by identifying a cystine-dense peptide capable of inhibiting the YAP:TEAD interaction at the heart of the oncogenic Hippo pathway, and possessing the potency and stability necessary for consideration as a drug development candidate. This platform provides the opportunity to screen cystine-dense peptides with drug-like qualities against targets that are implicated for the treatment of diseases, but are poorly suited for conventional approaches. Pathologies related to protein:protein interaction are hard to treat but cystine-dense peptides have the potential to disrupt such interactions. Here the authors develop a high-diversity mammalian cell screen for cystine-dense peptides with drug potential and use it to identify a YAP:TEAD inhibitor.
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影响因子：
2.4
作者：
Kim S;Kim KT
通讯作者：
Kim KT
影响因子：
2.9
作者：
Kimura RH;Levin AM;Cochran FV;Cochran JR
通讯作者：
Cochran JR
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
DOI：
10.3390/ph3041093
发表时间：
2010-04-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Gurrola GB;Capes EM;Zamudio FZ;Possani LD;Valdivia HH
通讯作者：
Valdivia HH