The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic.
J Med Chem. 2021 May 13;64(9):5710-5729. doi: 10.1021/acs.jmedchem.0c02184. Epub 2021 Apr 23.
(Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world's population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine-guanine-hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 μM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.
（Hp）是一种人类病原体，存在于世界上约 50%人口的胃黏膜中，导致胃炎、消化性溃疡和胃癌。当前药物的耐药性增加，促使人们寻找新的 Hp 药物靶点和治疗方法。一个目标是破坏核酸的产生，这可以通过阻碍 6-氧嘌呤核苷单磷酸的合成来实现，这些前体是 DNA 和 RNA 的合成物。这些代谢物由 Hp 黄嘌呤-鸟嘌呤-次黄嘌呤磷酸核糖基转移酶（XGHPRT）合成。在这里，评估了核苷膦酸，它们以低至 200 nM 的 值抑制该酶的活性。这些化合物的前药在基于细胞的测定中以 50 μM 的浓度抑制 Hp 的生长。已经确定了 HpXGHPRT 的动力学特性及其在缺乏和存在 9-[-（-3-膦丙基）-氨甲基-9-去氮次黄嘌呤]的情况下的 X 射线晶体结构，为新抗生素的开发提供了基础。
