Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments.
Efficient Ligand Discovery Using Sulfur(VI) Fluoride Reactive Fragments.
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DOI：
10.1021/acschembio.3c00034
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发表时间：
2023-09-15
影响因子：
4
通讯作者：
Bush, Jacob T.
中科院分区：
文献类型：
--
作者：
Aatkar, Arron;Vuorinen, Aini;Longfield, Oliver E.;Gilbert, Katharine;Peltier-Heap, Rachel;Wagner, Craig D.;Zappacosta, Francesca;Rittinger, Katrin;Chung, Chun-wa;House, David;Tomkinson, Nicholas C. O.;Bush, Jacob T.
硫（VI）氟化物（SFs）已成为有价值的亲电试剂，用于设计“超越半胱氨酸”的共价抑制剂，并为配体蛋白质组的扩展提供了潜力。由于SF靶向广泛的亲核氨基酸，因此它们提供了一种用于蛋白质共价修饰的方法，而不需要近端半胱氨酸残基。除此之外，反应性片段的文库提供了一种创新的方法，用于通过利用广泛的质谱分析方法来发现感兴趣的蛋白质的配体和工具。在此，我们报告了一种筛选方法，利用SF的独特属性，用于此目的。合成含SF的反应性片段的文库，并采用直接生物学工作流程来有效地鉴定CAII和BCL 6的命中化合物。进一步表征最有希望的命中，以建立共价修饰位点、修饰动力学和细胞中的靶标接合。晶体学用于获得这些反应性片段如何与其靶结合的详细分子理解。预期该筛选方案可用于加速发现“超越半胱氨酸”共价抑制剂。
Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of “beyond-cysteine” covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesized, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterized to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of “beyond-cysteine” covalent inhibitors.
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影响因子：
5.6
作者：
Lomelino CL;Supuran CT;McKenna R
通讯作者：
McKenna R
DOI：
10.1016/j.jbc.2021.100928
发表时间：
2021-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Pearce AC;Bamford MJ;Barber R;Bridges A;Convery MA;Demetriou C;Evans S;Gobbetti T;Hirst DJ;Holmes DS;Hutchinson JP;Jayne S;Lezina L;McCabe MT;Messenger C;Morley J;Musso MC;Scott-Stevens P;Manso AS;Schofield J;Slocombe T;Somers D;Walker AL;Wyce A;Zhang XP;Wagner SD
通讯作者：
Wagner SD
影响因子：
16.6
作者：
Douangamath A;Fearon D;Gehrtz P;Krojer T;Lukacik P;Owen CD;Resnick E;Strain-Damerell C;Aimon A;Ábrányi-Balogh P;Brandão-Neto J;Carbery A;Davison G;Dias A;Downes TD;Dunnett L;Fairhead M;Firth JD;Jones SP;Keeley A;Keserü GM;Klein HF;Martin MP;Noble MEM;O'Brien P;Powell A;Reddi RN;Skyner R;Snee M;Waring MJ;Wild C;London N;von Delft F;Walsh MA
通讯作者：
Walsh MA
影响因子：
7.3
作者：
Lanman, Brian A.;Allen, Jennifer R.;Cee, Victor J.
通讯作者：
Cee, Victor J.
影响因子：
15
作者：
Johansson, Henrik;Tsai, Yi-Chun Isabella;Rittinger, Katrin
通讯作者：
Rittinger, Katrin