The design of protozoan phosphoribosyltransferase inhibitors containing non-charged phosphate mimic residues.
The design of protozoan phosphoribosyltransferase inhibitors containing non-charged phosphate mimic residues.
复制标题
含有不带电荷的磷酸盐模拟残基的原生动物磷酸核糖基转移酶抑制剂的设计。
DOI：
10.1016/j.bmc.2022.117038
复制
发表时间：
2022
影响因子：
3.5
通讯作者：
Tyler,PeterC
中科院分区：
文献类型：
--
作者：
Gai,Sinan;Suthagar,Kajitha;Shaffer,KarlJ;Jiao,Wanting;Minnow,YacobaVT;Glockzin,Kayla;Maatouk,SeanW;Katzfuss,Ardala;Meek,ThomasD;Schramm,VernL;Tyler,PeterC
磷酸基团在生物过程中发挥着重要作用，包括保留在生物膜内。磷酸二酯连接核酸，磷酸基团的可逆转移对于能量代谢和细胞信号传导过程至关重要。磷酸化代谢中间体是代谢和疾病相关疾病的已知靶标，参与这些途径的酶可识别其催化位点的磷酸基团。针对这些酶的治疗可能需要带电（离子）实体来捕获离子底物的结合能。此类化合物不具有细胞渗透性，需要前药策略才能发挥治疗功效。原生动物寄生虫，如疟原虫和锥虫。无法从头合成嘌呤，只能依靠从宿主细胞中回收嘌呤来合成游离嘌呤碱基。嘌呤磷酸核糖转移酶（PPRTase）在嘌呤回收中发挥着至关重要的作用，并且是药物开发的潜在目标。在这里，我们尝试设计非离子型 PPRTase 抑制剂，并对 5'-磷酸核苷酸结合位点表现出亲和力。抑制剂设计基于已知的强效离子抑制剂、报道的磷酸盐模拟物和计算模型研究。
Phosphate groups play essential roles in biological processes, including retention inside biological membranes. Phosphodiesters link nucleic acids, and the reversible transfer of phosphate groups is essential in energy metabolism and cell-signalling processes. Phosphorylated metabolic intermediates are known targets for metabolic and disease-related disorders, and the enzymes involved in these pathways recognize phosphate groups in their catalytic sites. Therapeutics that target these enzymes can require charged (ionic) entities to capture the binding energy of ionic substrates. Such compounds are not cell-permeable and require pro-drug strategies for efficacy as therapeutics. Protozoan parasites such asPlasmodiumandTrypanosomaspp. are unable to synthesise purinesde novoand rely on the salvage of purines from the host cell to synthesise free purine bases. Purine phosphoribosyltransfereases (PPRTases) play a crucial role for purine salvage and are potential target for drug development. Here we present attempts to design inhibitors of PPRTases that are non-ionic and show affinity for the nucleotide 5′-phosphate binding site. Inhibitor design was based on known potent ionic inhibitors, reported phosphate mimics and computational modelling studies.