Engineered protein-small molecule conjugates empower selective enzyme inhibition.
Engineered protein-small molecule conjugates empower selective enzyme inhibition.
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DOI：
10.1016/j.chembiol.2021.07.013
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发表时间：
2022-02-17
影响因子：
8.6
通讯作者：
Hackel BJ
中科院分区：
文献类型：
--
作者：
Lewis AK;Harthorn A;Johnson SM;Lobb RR;Hackel BJ
特定的、强有力的配体推动了精确医学和基础生物学的发展。蛋白质、多肽和小分子构成了有效的配体类。然而，更大的分子多样性将有助于对配体的追求，以诱导针对具有挑战性的目标的精确生物活性。我们展示了一个发现蛋白质-小分子(棱镜)杂交体的平台，将独特的药效团活性和形状与受限制的、可高效工程的蛋白质结合在一起。纤维连接蛋白蛋白文库是用一个半胱氨酸通过马来酰亚胺-聚乙二醇联接物与乙酰唑胺偶联的酵母展示的。磁性分选和流式细胞术分选使特定的结合剂富含碳酸酐酶异构体。分离的棱镜显示出对碳酸酐酶异构体的有效、特异的抑制，其疗效优于单独使用乙酰唑胺或蛋白质，包括80倍的特异性增加和9倍的效力增加。棱镜被设计成具有多个接头长度、蛋白质结合位点和针对两种不同异构体的序列，这揭示了平台的灵活性和分子设计的影响。棱镜提高了高效可工程配体的分子多样性。Lewis和Harthorn等人。展示了一个发现蛋白质-小分子杂交物的平台，这种杂交物将药效团活性与可工程蛋白质相结合，以实现优于任何一种单独成分的效力和特异性。针对两种酶的具有多个连接子长度、接合位点和蛋白质序列的杂交物表现出平台灵活性和设计影响。
Specific, potent ligands drive precision medicine and fundamental biology. Proteins, peptides, and small molecules constitute effective ligand classes. Yet greater molecular diversity would aid the pursuit of ligands to elicit precise biological activity against challenging targets. We demonstrate a platform to discover protein-small molecule (PriSM) hybrids to combine unique pharmacophore activities and shapes with constrained, efficiently engineerable proteins. A fibronectin protein library is yeast displayed with a single cysteine coupled to acetazolamide via a maleimide-poly(ethylene glycol) linker. Magnetic and flow cytometric sorts enrich specific binders to carbonic anhydrase isoforms. Isolated PriSMs exhibit potent, specific inhibition of carbonic anhydrase isoforms with superior efficacy to acetazolamide or protein alone including an 80-fold specificity increase and 9-fold potency gain. PriSMs are engineered with multiple linker lengths, protein conjugation sites, and sequences against two different isoforms, which reveals platform flexibility and impacts of molecular designs. PriSMs advance the molecular diversity of efficiently engineerable ligands. Lewis and Harthorn et al. demonstrate a platform to discover protein-small molecule hybrids that merge pharmacophore activity with engineerable proteins to achieve potency and specificity superior to either component alone. Hybrids with multiple linker lengths, conjugation sites, and protein sequences against two enzymes reveal platform flexibility and design impacts.
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影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
影响因子：
14.8
作者：
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通讯作者：
Winter, Greg
影响因子：
2.4
作者：
Jespers, L;Bonnert, TP;Winter, G
通讯作者：
Winter, G
影响因子：
2.9
作者：
deGruyter JN;Malins LR;Baran PS
通讯作者：
Baran PS
影响因子：
4
作者：
Islam M;Kehoe HP;Lissoos JB;Huang M;Ghadban CE;Berumen Sánchez G;Lane HZ;Van Deventer JA
通讯作者：
Van Deventer JA