ddhCTP

ddhCTP is a novel antiviral molecule produced by viperin in the early stages of the innate immune response and is a chain terminator for RNA-dependent RNA polymerases (RdRps) of multiple flaviviruses^[1]. Viperin is a member of the free radical S-adenosyl-L-methionine (SAM) enzyme superfamily and an interferon-inducible protein that is involved in inhibiting the replication of a variety of RNA and DNA viruses, including dengue virus, West Nile virus, Zika virus, hepatitis C virus, influenza A virus, rabies virus, and HIV^{[2, 3]}. Modification of ddhCTP involves removal of the 3'-hydroxyl group, thereby preventing subsequent nucleotide addition to the nascent chain, acting as an RNA chain terminator inhibitor^[4]. ddhCTP is a nucleoside analog with K_i values of 1.32μM and 0.034μM for DNA polymerase β and DNA polymerase γ, respectively^[5]. ddhCTP can inhibit the NAD⁺-dependent activity of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH)^[6].

References:
[1] Honarmand Ebrahimi K, Vowles J, Browne C, et al. ddhCTP produced by the radical‐SAM activity of RSAD2 (viperin) inhibits the NAD+‐dependent activity of enzymes to modulate metabolism[J]. FEBS letters, 2020, 594(10): 1631-1644.
[2] Gizzi A S, Grove T L, Arnold J J, et al. A naturally occurring antiviral ribonucleotide encoded by the human genome[J]. Nature, 2018, 558(7711): 610-614.
[3] Kennelly S A, Sawyer J M, Payne A F, et al. Development of 3′-Deoxy-3′, 4′-didehydro-nucleoside Prodrug Inhibitors of West Nile and Zika Viruses[J]. ACS Medicinal Chemistry Letters, 2024, 15(8): 1334-1339.
[4] Ciardullo G, Parise A, Prejanò M, et al. Viral RNA replication suppression of SARS-CoV-2: Atomistic insights into inhibition mechanisms of RdRp machinery by ddhCTP[J]. Journal of Chemical Information and Modeling, 2024, 64(5): 1593-1604.
[5] Cherrington J M, Allen S J, McKee B H, et al. Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylemthoxypropyl) cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases β and γ[J]. Biochemical pharmacology, 1994, 48(10): 1986-1988.
[6] Palmer C S. Innate metabolic responses against viral infections[J]. Nature Metabolism, 2022, 4(10): 1245-1259.

ddhCTP是一种新型抗病毒分子，由Viperin（蝰蛇蛋白）在先天免疫反应的早期阶段产生，是多种黄病毒的RNA依赖性RNA聚合酶（RdRps）的链终止子^[1]。Viperin是自由基S-腺苷-L-甲硫氨酸（SAM）酶超家族的成员，是一种干扰素诱导蛋白，参与抑制多种RNA和DNA病毒的复制，包括登革热病毒、西尼罗河病毒、寨卡病毒、丙型肝炎病毒、甲型流感病毒、狂犬病病毒和艾滋病毒^{[2, 3]}。ddhCTP的修饰涉及去除3'-羟基，从而防止随后的核苷酸添加到新生链中，充当RNA链终止子抑制剂^[4]。ddhCTP是一种核苷类似物，对DNA聚合酶β和DNA聚合酶γ的K_i值分别为1.32μM和0.034μM^[5]。ddhCTP可抑制糖酵解酶甘油醛3-磷酸脱氢酶 （GAPDH）的NAD⁺依赖性活性^[6]。