Structure-based design of guanosine analogue inhibitors targeting GTP cyclohydrolase IB towards a new class of antibiotics.
Structure-based design of guanosine analogue inhibitors targeting GTP cyclohydrolase IB towards a new class of antibiotics.
复制标题
针对 GTP 环水解酶 IB 的鸟苷类似物抑制剂的基于结构的设计，成为一类新型抗生素。
DOI：
10.1016/j.bmcl.2019.126818
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发表时间：
2020
影响因子：
2.7
通讯作者：
Purse,ByronW
中科院分区：
文献类型：
--
作者：
Samaan,GeorgeN;Paranagama,Naduni;Haque,Ayesha;Hecht,DavidA;Swairjo,ManalA;Purse,ByronW
GTP 环水解酶 (GCYH-I) 是叶酸生物合成途径中的一种酶，之前并未被用作抗生素靶点，尽管包括淋病奈瑟菌在内的几种病原体使用一种在结构上与人类同源物 GCYH-IA 不同的 GCYH-IB 形式。将 GCYH-IA 和 -IB 的晶体结构与结合的 nM 抑制剂 8-oxo-GTP 进行比较表明，GCYH-IB 的活性位点更大且形状不同。基于这些结构信息，我们设计并合成了一小组在 O6 和 O8 处具有醚键的 8-oxo-G 衍生物，预计可以从 GCYH-IB 的扩展活性位点取代水分子。这些化合物中最有效的 G3 对 GCYH-IB 具有选择性，支持了 GCYH-IB 的有效和选择性抑制剂可以构成一类新的小分子抗生素的前提。
GTP cyclohydrolase (GCYH-I) is an enzyme in the folate biosynthesis pathway that has not been previously exploited as an antibiotic target, although several pathogens including N. gonorrhoeae use a form of the enzyme GCYH-IB that is structurally distinct from the human homologue GCYH-IA. A comparison of the crystal structures of GCYH-IA and -IB with the nM inhibitor 8-oxo-GTP bound shows that the active site of GCYH-IB is larger and differently shaped. Based on this structural information, we designed and synthesized a small set of 8-oxo-G derivatives with ether linkages atO6andO8expected to displace water molecules from the expanded active site of GCYH-IB. The most potent of these compounds,G3, is selective for GCYH-IB, supporting the premise that potent and selective inhibitors of GCYH-IB could constitute a new class of small molecule antibiotics.