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Immucillins in Infectious Diseases
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-12-05 00:00:00 , DOI: 10.1021/acsinfecdis.7b00172 Gary B. Evans 1 , Peter C. Tyler 1 , Vern L. Schramm 2
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-12-05 00:00:00 , DOI: 10.1021/acsinfecdis.7b00172 Gary B. Evans 1 , Peter C. Tyler 1 , Vern L. Schramm 2
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The Immucillins are chemically stable analogues that mimic the ribocation and leaving-group features of N-ribosyltransferase transition states. Infectious disease agents often rely on ribosyltransferase chemistry in pathways involving precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or synthetic pathways with nucleoside intermediates. Here, we review three infectious agents and the use of the Immucillins to taget enzymes essential to the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase (PNP) inhibitor that blocks purine salvage and shows clinical potential for treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in the host and in parasite cells leads to apurinic starvation and death. Second, Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone, an essential electron transfer agent, in a pathway requiring aminofutalosine nucleoside hydrolysis. Inhibitors of the H. pylori methylthioadenosine nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of menaquinone by the aminofutalosine pathway does not occur in most bacteria populating the human gut microbiome. Thus, MTAN inhibitors provide high-specificity antibiotics for H. pylori and are not expected to disrupt the normal gut bacterial flora. Third, Immucillin-A was designed as a transition state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral screens, Immucillin-A was shown to act as a prodrug. It is active against filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted to the triphosphate, is incorporated into the viral transcript, and functions as an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has entered clinical trials for use as an antiviral. We also summarize other Immucillins that have been characterized in successful clinical trials for T-cell lymphoma and gout. The human trials support the potential development of the Immucillins in infectious diseases.
中文翻译：
伊米西林在传染病中的作用
伊莫西林是化学稳定的类似物，其模仿N-核糖基转移酶过渡态的核糖基化和离去基团特征。传染病原通常在涉及核酸前体合成，核酸前体的挽救或具有核苷中间体的合成途径的途径中依赖核糖基转移酶化学。在这里，我们审查了三种传染病原体以及伊莫西林对寄生虫必不可少的标记酶的使用。首先，DADMe-Immucillin-G是一种嘌呤核苷磷酸化酶（PNP）抑制剂，可阻止嘌呤的挽救并显示出治疗疟原虫恶性疟原虫的临床潜力，是一种嘌呤营养缺陷型，需要次黄嘌呤来进行嘌呤核苷酸合成。宿主和寄生虫细胞中PNP的抑制会导致嘌呤饥饿和死亡。其次，幽门螺杆菌是人类溃疡的病原体，它在需要氨基富他糖核苷水解的途径中合成了必需的电子转移剂甲萘醌。幽门螺杆菌甲基硫代腺苷核苷酶（MTAN）的抑制剂是这种生物的强大抗生素。在大多数人类肠道微生物组中，大多数细菌都不会通过氨基富他糖苷途径合成甲萘醌。因此，MTAN抑制剂可为幽门螺杆菌提供高特异性抗生素并且不会破坏正常的肠道细菌菌群。第三，将Immucillin-A设计为来自阴道毛滴虫的非典型PNP的过渡态类似物。在抗病毒筛选中，Immucillin-A被证明是前药。它对丝状病毒和黄病毒具有活性。在病毒感染的细胞中，Immucillin-A被转化为三磷酸，被整合到病毒转录物中，并作为RNA依赖性RNA聚合酶的非典型链终止剂。Immucillin-A已进入临床试验以用作抗病毒药。我们还总结了在成功的T细胞淋巴瘤和痛风临床试验中表征的其他伊西林。人体试验支持Immucillins在传染病中的潜在发展。
更新日期：2017-12-05
中文翻译：
伊米西林在传染病中的作用
伊莫西林是化学稳定的类似物，其模仿N-核糖基转移酶过渡态的核糖基化和离去基团特征。传染病原通常在涉及核酸前体合成，核酸前体的挽救或具有核苷中间体的合成途径的途径中依赖核糖基转移酶化学。在这里，我们审查了三种传染病原体以及伊莫西林对寄生虫必不可少的标记酶的使用。首先，DADMe-Immucillin-G是一种嘌呤核苷磷酸化酶（PNP）抑制剂，可阻止嘌呤的挽救并显示出治疗疟原虫恶性疟原虫的临床潜力，是一种嘌呤营养缺陷型，需要次黄嘌呤来进行嘌呤核苷酸合成。宿主和寄生虫细胞中PNP的抑制会导致嘌呤饥饿和死亡。其次，幽门螺杆菌是人类溃疡的病原体，它在需要氨基富他糖核苷水解的途径中合成了必需的电子转移剂甲萘醌。幽门螺杆菌甲基硫代腺苷核苷酶（MTAN）的抑制剂是这种生物的强大抗生素。在大多数人类肠道微生物组中，大多数细菌都不会通过氨基富他糖苷途径合成甲萘醌。因此，MTAN抑制剂可为幽门螺杆菌提供高特异性抗生素并且不会破坏正常的肠道细菌菌群。第三，将Immucillin-A设计为来自阴道毛滴虫的非典型PNP的过渡态类似物。在抗病毒筛选中，Immucillin-A被证明是前药。它对丝状病毒和黄病毒具有活性。在病毒感染的细胞中，Immucillin-A被转化为三磷酸，被整合到病毒转录物中，并作为RNA依赖性RNA聚合酶的非典型链终止剂。Immucillin-A已进入临床试验以用作抗病毒药。我们还总结了在成功的T细胞淋巴瘤和痛风临床试验中表征的其他伊西林。人体试验支持Immucillins在传染病中的潜在发展。
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