Chemoenzymatic Synthesis of 3′-Deoxy-3′,4′-didehydro-cytidine triphosphate (ddhCTP)

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-07-25 DOI:10.1021/acsbiomedchemau.3c00014
James H. Lee, James M. Wood, Steven C. Almo, Gary B. Evans, Lawrence D. Harris and Tyler L. Grove*, 
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Abstract

3′-Deoxy-3′,4′-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin during the early stages of the innate immune response. ddhCTP has been shown to act as a chain terminator of flavivirus RNA-dependent RNA polymerases. To date, synthesis of ddhCTP requires complicated synthetic protocols or isolation of the enzyme viperin to catalyze the production of ddhCTP from CTP. Recombinant viperin approaches preclude the production of highly pure ddhCTP (free of contaminants such as CTP), whereas the chemical synthesis involves techniques or equipment not readily available to most laboratories. Herein, we describe the chemoenzymatic synthesis of ddhCTP, starting from commercially available ddhC. We utilize these methods to produce milligram quantities of ddhCTP, ddhCDP, and ddhCMP. Using purified semisynthetic ddhCTP and fully synthetic ddhCTP, we also show ddhCTP does not inhibit NAD+-dependent enzymes such as glyceraldehyde 3-phosphate dehydrogenase, malate dehydrogenase, or lactate dehydrogenase, contrary to a recent report.

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化学酶法合成3′-脱氧-3′,4′-二脱氢胞苷三磷酸(ddhCTP)
3′-脱氧-3′,4′-二氢胞苷三磷酸(ddhCTP)是一种新型抗病毒分子,由viperin酶在先天免疫反应的早期阶段产生。ddhCTP已被证明是黄病毒RNA依赖性RNA聚合酶的链终止子。迄今为止,ddhCTP的合成需要复杂的合成方案或分离酶viperin来催化由CTP产生ddhCTP。重组viperin方法排除了高纯度ddhCTP(不含CTP等污染物)的生产,而化学合成涉及大多数实验室无法获得的技术或设备。在此,我们描述了ddhCTP的化学酶合成,从市售的ddhC开始。我们利用这些方法生产毫克量的ddhCTP、ddhCDP和ddhCMP。与最近的一份报告相反,使用纯化的半合成ddhCTP和全合成ddhCT,我们还表明ddhCTP不会抑制NAD+依赖性酶,如甘油醛3-磷酸脱氢酶、苹果酸脱氢酶或乳酸脱氢酶。
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ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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