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Nucleic Acids Research 2005 33(11):3550-3560; doi:10.1093/nar/gki657
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Published online 21 June 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs

Andrzej Grajkowski, Joao Pedras-Vasconcelos1, Vivian Wang1, Cristina Ausín, Sonja Hess2, Daniela Verthelyi1 and Serge L. Beaucage*

Laboratory of Chemistry, Center for Drug Evaluation and Research, Food and Drug Administration 8800 Rockville Pike, Bethesda, MD 20892, USA 1Laboratory of Immunology, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration 8800 Rockville Pike, Bethesda, MD 20892, USA 2Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health 9000 Rockville Pike, Bethesda, MD 20892, USA

*To whom correspondence should be addressed. Tel: +1 301 827 5162; Fax: +1 301 480 3256; Email: beaucage{at}cber.fda.gov

Received February 14, 2005. Revised May 9, 2005. Accepted May 26, 2005.

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.

This paper is dedicated to Professor Wojciech J. Stec on the occasion of his 65th birthday.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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M. Puig, A. Grajkowski, M. Boczkowska, C. Ausin, S. L. Beaucage, and D. Verthelyi
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