Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs.
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 degrees 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.
Laboratory of Chemistry, Center for Drug Evaluation and Research, Food and Drug Administration 8800 Rockville Pike, Bethesda, MD 20892, USA.
Andrzej
A
Grajkowski
Joao
J
Pedras-Vasconcelos
Vivian
V
Wang
Cristina
C
Ausín
Sonja
S
Hess
Daniela
D
Verthelyi
Serge L
SL
Beaucage
D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006358:Hot Temperature; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000627:therapeutic use*; D011355:Prodrugs / Q000737:chemistry* / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000890:Anti-Infective Agents; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D011355:Prodrugs