Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs.
Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs.
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含热溶解CpG的DNA寡核苷酸作为潜在的免疫治疗前药。
DOI：
10.1093/nar/gki657
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发表时间：
2005
影响因子：
14.9
通讯作者：
Beaucage, SL
中科院分区：
文献类型：
--
作者：
Grajkowski, A;Pedras-Vasconcelos, J;Wang, VV;Ausín, C;Hess, S;Verthelyi, D;Beaucage, SL
以磷酰胺1a-d为原料，采用固相技术制备了2-（n -甲酰基- n -甲基）氨基乙基硫代磷酸保护基（CpG ODN fma1555）功能化的含CpG的DNA寡核苷酸。该寡核苷酸通过热解裂解2-（n -甲酰基- n -甲基）氨基乙基硫代磷酸酯保护基团，转化为免疫调节的CpG ODN 1555，从而发挥了前药的作用。这种转化发生在37°C，半衰期为73 h。CpG ODN fma1555的免疫刺激特性在两个体内实验中进行了评估，其中一个实验包括用活的利什曼原虫在小鼠耳中攻击。局部皮内给药CpG ODN fma1555与CpG ODN 1555在随时间减少利什曼原虫病变大小方面同样有效。在另一种感染模型中，CpG ODN 1555在感染后第0天至第3天给药可防止感染tacaribe的小鼠死亡（存活率为43%）。感染前3天给予CpG ODN fma1555可改善免疫保护（60-70%生存率）。此外，在该模型中，CpG ODN fma1555和CpG ODN 1555共同给药增加了治疗Tacaribe病毒感染的窗口期，从而支持使用热解寡核苷酸作为前药有效治疗感染性疾病。
A CpG-containing DNA oligonucleotide functionalized with the 2-(N-formyl-N-methyl)aminoethyl thiophosphate protecting group (CpG ODN fma1555) was prepared from phosphoramidites 1a–d using solid-phase techniques. The oligonucleotide behaved as a prodrug by virtue of its conversion to the well-studied immunomodulatory CpG ODN 1555 through thermolytic cleavage of the 2-(N-formyl-N-methyl)aminoethyl thiophosphate protecting group. Such a conversion occurred at 37°C with a half-time of 73 h. The immunostimulatory properties of CpG ODN fma1555 were evaluated in two in vivo assays, one of which consisted of mice challenged in the ear with live Leishmania major metacyclic promastigotes. Local intradermal administration of CpG ODN fma1555 was as effective as that of CpG ODN 1555 in reducing the size of Leishmania lesions over time. In a different infectious model, CpG ODN 1555 prevented the death of Tacaribe-infected mice (43% survival) when administered between day 0 and 3 post infection. Administration of CpG ODN fma1555 three days before infection resulted in improved immunoprotection (60–70% survival). Moreover, co-administration of CpG ODN fma1555 and CpG ODN 1555 in this model increased the window for therapeutic treatment against Tacaribe virus infection, and thus supports the use of thermolytic oligonucleotides as prodrugs in the effective treatment of infectious diseases.
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影响因子：
3.6
作者：
IYER, RP;PHILLIPS, LR;BEAUCAGE, SL
通讯作者：
BEAUCAGE, SL
DOI：
10.1039/b101754n
发表时间：
2001-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
Ora, M;Mäki, E;Lönnberg, H
通讯作者：
Lönnberg, H
影响因子：
46.9
作者：
Agrawal, S;Kandimalla, ER
通讯作者：
Kandimalla, ER
影响因子：
2.7
作者：
BARBER, I;RAYNER, B;IMBACH, JL
通讯作者：
IMBACH, JL
影响因子：
14.9
作者：
Boal, JH;Wilk, A;Beaucage, SL
通讯作者：
Beaucage, SL