Design and Development of Stable, Water-soluble, Human Toll-like Receptor 2-Specific, Monoacyl Lipopeptides as Candidate Vaccine Adjuvants

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Issue Date
2013-07-25Author
Salunke, Deepak B.
Connelly, Seth W.
Shukla, Nikunj M.
Hermanson, Alec R.
Fox, Lauren M.
David, Sunil A.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900254k.
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Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of TLR2 are devoid of significant pro-inflammatory activity in ex vivo human blood models, and yet potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead, but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble, human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.
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Citation
Salunke, D. B., Connelly, S. W., Shukla, N. M., Hermanson, A. R., Fox, L. M., & David, S. A. (2013). Design and Development of Stable, Water-soluble, Human Toll-like Receptor 2-Specific, Monoacyl Lipopeptides as Candidate Vaccine Adjuvants. Journal of Medicinal Chemistry, 56(14), 10.1021/jm400620g. http://doi.org/10.1021/jm400620g
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