<br>SAMHD1 dNTPase 活性和核酸结合的脱氧鸟苷连接的双功能抑制剂,ACS Chemical Biology

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SAMHD1 dNTPase 活性和核酸结合的脱氧鸟苷连接的双功能抑制剂
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2023-05-26 , DOI: 10.1021/acschembio.3c00118
Matthew Egleston ₁ , Linghao Dong ₁ , A Hasan Howlader ₂ , Shridhar Bhat ₁ , Benjamin Orris ₁ , Mario A Bianchet ₃ , Marc M Greenberg ₂ , James T Stivers ₁

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无菌 α 基序组氨酸-天冬氨酸结构域蛋白 1 （SAMHD1）是一种脱氧核苷酸三磷酸水解酶，以单聚体、二聚体和四聚体形式存在。它通过 GTP 与每个单体亚基上的 A1 变构位点结合而被激活，从而诱导二聚化，这是 dNTP 诱导的四聚化的前提。SAMHD1 是一个经过验证的药物靶点，源于其对许多抗癌核苷药物的失活，从而导致耐药性。该酶还具有单链核酸结合功能，可通过多种机制促进 RNA 和 DNA 稳态。为了发现 SAMHD1 的小分子抑制剂，我们筛选了一个定制的 ∼69 000 化合物库的 dNTPase 抑制剂。令人惊讶的是，这项工作没有产生可行的结果，并表明存在发现小分子抑制剂的特殊障碍。然后，我们采用基于片段的合理抑制剂设计方法，使用脱氧鸟苷（dG） A1 位点靶向片段。通过将 5′-磷酸基丙胺 dG 片段（dGpC₃NH₂）偶联到 376 羧酸（RCOOH）合成靶向化学库。直接筛选产物（dGpC₃NHCO-R）产生 9 个初始命中，其中 1 个（R = 3-（3′-溴-[1,1′-联苯]），5a）被广泛研究。Amide 5a 是一种竞争性抑制剂，可防止 GTP 与 A1 位点结合，并诱导缺乏四聚化的无活性二聚体。令人惊讶的是，5a 还阻止了 ssDNA 和 ssRNA 的结合，表明 SAMHD1 的 dNTPase 和核酸结合功能可以被单个小分子破坏。 SAMHD1-5a 复合物的结构表明，联苯片段阻碍了四聚化所需的 C 端叶的构象变化。

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Deoxyguanosine-Linked Bifunctional Inhibitor of SAMHD1 dNTPase Activity and Nucleic Acid Binding

Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase that exists in monomeric, dimeric, and tetrameric forms. It is activated by GTP binding to an A1 allosteric site on each monomer subunit, which induces dimerization, a prerequisite for dNTP-induced tetramerization. SAMHD1 is a validated drug target stemming from its inactivation of many anticancer nucleoside drugs leading to drug resistance. The enzyme also possesses a single-strand nucleic acid binding function that promotes RNA and DNA homeostasis by several mechanisms. To discover small molecule inhibitors of SAMHD1, we screened a custom ∼69 000-compound library for dNTPase inhibitors. Surprisingly, this effort yielded no viable hits and indicated that exceptional barriers for discovery of small molecule inhibitors existed. We then took a rational fragment-based inhibitor design approach using a deoxyguanosine (dG) A1 site targeting fragment. A targeted chemical library was synthesized by coupling a 5′-phosphoryl propylamine dG fragment (dGpC₃NH₂) to 376 carboxylic acids (RCOOH). Direct screening of the products (dGpC₃NHCO-R) yielded nine initial hits, one of which (R = 3-(3′-bromo-[1,1′-biphenyl]), 5a) was investigated extensively. Amide 5a is a competitive inhibitor against GTP binding to the A1 site and induces inactive dimers that are deficient in tetramerization. Surprisingly, 5a also prevented ssDNA and ssRNA binding, demonstrating that the dNTPase and nucleic acid binding functions of SAMHD1 can be disrupted by a single small molecule. A structure of the SAMHD1-5a complex indicates that the biphenyl fragment impedes a conformational change in the C-terminal lobe that is required for tetramerization.

更新日期：2023-05-26

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