Tubercidin is a pyrrolopyrimidine nucleoside analog with significant activity against schistosomal infections.?It has also been tested as a cancer chemotherapeutic agent, but its utility has been limited by nephrotoxicity[8].?As one of the most potent inhibitors of human liver SAH-hydrolase, Tubercidin enters cells via nucleoside transporters[7].?Upon intracellular metabolism of tubercidin to its mono, di, and tri-phosphate esters, it can substitute for adenosine nucleotides, and thereby interfere in the synthesis of DNA, RNA, and protein. As a toxic adenosine analog with antiviral, antitrypanosomal, and antifungal functions.?Inhibits multiple metabolic processes which includes: RNA processing, nucleic acid synthesis, protein synthesis, and methylation of tRNA through intracellular incorporation into nucleic acids.?Acts as a plant antifungal, inhibits mammalian SAHH (SAH hydrolase), and blocks purine biosynthesis in Candida famata[1].Tubercidin has been studied for antiviral and anticancer properties, is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties[4,5].
In vitro, tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin.?At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM.?Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM.?NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter[3].Continuous exposure for 14 days to tubercidin alone is highly toxic to both human CFU-GM and BFU-E.?The IC50s of tubercidin are 3.4±1.7 and 3.7±0.2 nM for CFU-GM and BFU-E, respectively.?Tubercidin also has a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells in vitro[6].?The inhibitor tubercidin proved to be highly antiviral against SARS-CoV-2, Tubercidin is a broad-spectrum MTase inhibitor active against both NSP16 and MTr1.tubercidin potently inhibited both NSP16 and MTr1 in vitro, further emphasizing that a concomitant inhibition of NSP16 and MTr1 is pivotal for effective antiviral treatment.[2,3]
Host toxicity of the dose regimen of tubercidin plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis.?Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection.?Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium.
参考文献:
[1]: Stahmann KP, Revuelta JL,et,al. Three biotechnical processes using Ashbya gossypii, Candida famata, or Bacillus subtilis compete with chemical riboflavin production. Appl Microbiol Biotechnol. 2000 May;53(5):509-16. doi: 10.1007/s002530051649. PMID: 10855708.
[2]:Bergant V, Yamada S, et,al. Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases. EMBO J. 2022 Jul 14:e111608. doi: 10.15252/embj.2022111608. Epub ahead of print. PMID: 35833542; PMCID: PMC9350232.
[3]:Schultz DC, Johnson RM, et,al. Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2. Nature. 2022 Apr;604(7904):134-140. doi: 10.1038/s41586-022-04482-x. Epub 2022 Feb 7. PMID: 35130559.
[4]:Olsen DB, Eldrup AB, et,al. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob Agents Chemother. 2004 Oct;48(10):3944-53. doi: 10.1128/AAC.48.10.3944-3953.2004. PMID: 15388457; PMCID: PMC521892.
[5]: Vittori S, Dal Ben D, et,al. Antiviral properties of deazaadenine nucleoside derivatives. Curr Med Chem. 2006;13(29):3529-52. doi: 10.2174/092986706779026228. PMID: 17168721.
[6]: el Kouni MH, Diop D, et,al. Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis. Antimicrob Agents Chemother. 1989 Jun;33(6):824-7. doi: 10.1128/AAC.33.6.824. PMID: 2764531; PMCID: PMC284239.
[7]: Fabianowska-Majewska K, Duley JA, et,al. Effects of novel anti-viral adenosine analogues on the activity of S-adenosylhomocysteine hydrolase from human liver. Biochem Pharmacol. 1994 Aug 30;48(5):897-903. doi: 10.1016/0006-2952(94)90360-3. PMID: 8093102.
[8]: Bisel HF, Ansfield FJ, et,al. Clinical studies with tubercidin administered by direct intravenous injection. Cancer Res. 1970 Jan;30(1):76-8. PMID: 4917978.
Tubercidin 是一种吡咯并嘧啶核苷类似物，对血吸虫感染具有显着活性。它还作为癌症化疗剂进行了测试，但其实用性受到肾毒性的限制[8]。作为人类肝脏 SAH 水解酶最有效的抑制剂之一，Tubercidin 通过核苷转运蛋白进入细胞[7]。结核菌素在细胞内代谢为单磷酸酯、二磷酸酯和三磷酸酯后，可替代腺苷核苷酸，从而干扰 DNA、RNA 和蛋白质的合成。作为具有抗病毒、抗锥虫和抗真菌功能的有毒腺苷类似物。抑制多种代谢过程，包括:RNA 加工、核酸合成、蛋白质合成和通过细胞内掺入核酸的 tRNA 甲基化。作为植物抗真菌剂，抑制哺乳动物 SAHH（SAH 水解酶），并阻断 Candida famata[1] 中的嘌呤生物合成。已研究结核菌素的抗病毒和抗癌特性，是一种有效的选择性肝炎抑制剂具有优良药代动力学特性的C病毒复制[4,5].
在体外，单独使用结核菌素对骨髓和红系人骨髓祖细胞具有直接的剂量依赖性抑制作用，并且对粒细胞-巨噬细胞 CFU (CFU-GM) 和红系爆发形成单位具有一致的抑制作用 (50%) ( BFU-E) 发生在 2 至 3 nM 结核菌素。在较高剂量下，BFU-E 比 CFU-GM 对结核菌素毒性更敏感。 BFU-E 菌落的完全抑制 (99%) 发生在 10 nM 结核菌素，而 CFU-GM 的完全抑制发生在 100 nM。 10 至 100 nM 的 NBMPR-P 以剂量依赖性方式保护 CFU-GM 和 BFU-E 免受结核菌素的毒性[3]。单独连续暴露于结核菌素 14 天对人类和人类都有剧毒CFU-GM 和 BFU-E。结核菌素对 CFU-GM 和 BFU-E 的 IC50 分别为 3.4±1.7 和 3.7±0.2 nM。 Tubercidin 在体外对髓系和红系人骨髓祖细胞也具有直接的剂量依赖性抑制作用[6]。抑制剂 tubercidin 被证明对 SARS-CoV-2 具有高度抗病毒作用，Tubercidin 是一种广谱 MTase 抑制剂，对 NSP16 和 MTr1 均有活性。tubercidin 在体外有效抑制 NSP16 和 MTr1，进一步强调同时抑制 NSP16 和 MTr1是有效抗病毒治疗的关键。[2,3]
用于联合治疗血吸虫病的结核菌素加硝基苄硫肌苷 5'-单磷酸盐 (NBMPR-P) 剂量方案的宿主毒性。 NBMPR-P（每天 25 毫克/千克）的共同给药保护小鼠免受结核菌素的致死性，并允许第二次重复该方案，存活率为 100%，直到小鼠在第一次注射后 22 天被处死。血液化学、血液学研究和组织学检查均未显示肝脏、肾脏、脾脏、胰腺、肠系膜或腹膜间皮损伤的证据。
| Cell experiment [1]: | |
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Cell lines |
Human bone marrow cells |
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Preparation Method |
In the protection studies, cells are exposed to 10 nM of tubercidin in the presence or absence of various doses of NBMPR-P. Cells are continuously exposed to drugs for 14 days in a humidified atmosphere of 5% C02-95% air at 37°c. Colonies of CFU-GM (250 cells) and BFU-E (30 hemoglobinized cells) are counted with an inverted microscope. |
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Reaction Conditions |
10 nM of tubercidin?；14 days in a humidified atmosphere of 5% C02-95% air at 37°c |
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Applications |
Tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin. At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM. NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter. |
| Animal experiment [2]: | |
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Animal models |
35 female (20- to 25-g) CD1 mice |
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Preparation Method |
Three groups of mice were used, each consisting of 35 female (20- to 25-g) CD1 mice, The first group received four successive daily intraperitoneal injections of tubercidin (5 mg/kg per dose) plus NBMPR-P (25 mg/kg per dose) ;?the regimen was repeated after a 10-day rest period .?The second group received four daily injections of tubercidin (5 mg/kg per dose) alone, but the regimen could not be repeated owing to the death of mice within 3 to 5 days of the initiation of treatment.?The third group (controls) received saline solution (0.9% NaCI).?Drugs were prepared and administered as previously described.?All mice that survived were sacrificed 4 days after the last injection.?Whole blood was obtained by cardiac puncture and collected in a Unopette microcollection system. |
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Dosage form |
5 mg/kg per dose |
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Applications |
Tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis was examined in vivo in mice and in vitro with human bone marrow progenitor cells.?Four successive daily intraperitoneal injections of tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive peritonitis and intestinal obstruction secondary to abdominal adhesions.?Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection.?Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. |
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参考文献: [1]. el Kouni MH, Diop D, et,al. Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis. Antimicrob Agents Chemother. 1989 Jun;33(6):824-7. doi: 10.1128/AAC.33.6.824. PMID: 2764531; PMCID: PMC284239. |
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