Design and development of stable, water-soluble, human Toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants
| Autor: | Alec R. Hermanson, Seth W. Connelly, Lauren M. Fox, Sunil A. David, Deepak B. Salunke, Nikunj M. Shukla |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_treatment
Pharmacology Article Proinflammatory cytokine chemistry.chemical_compound Lipopeptides Mice Structure-Activity Relationship Immune system Antigen Adjuvants Immunologic Drug Discovery medicine Animals Humans Toll-like receptor Mice Inbred BALB C Vaccines Innate immune system Chemistry Lipopeptide Toll-Like Receptor 2 Mice Inbred C57BL TLR2 Drug Design Molecular Medicine Rabbits Adjuvant |
| Zdroj: | Journal of medicinal chemistry. 56(14) |
| ISSN: | 1520-4804 |
| Popis: | 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 Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are 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. |
| Databáze: | OpenAIRE |
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