| Autor: |
Luis Brito, Ennio De Gregorio, Susanna Aprea, Samuele Calabrό, Chun Li, Francesco Doro, Sina Bavari, Miller Andrew T, David A. G. Skibinski, Rekha G. Panchal, Donatello Laera, M. Lamine Mbow, Simone Bufali, Ann E. Herman, Ugo D'Oro, Michael P. Cooke, Elaine Tritto, Padma Malyala, Brunella Brunelli, Elisabetta Monaci, Alex Cortez, Gillis R. Otten, Sara Valentini, Travis K. Warren, Christophe M. Filippi, Nicholas Valiante, Yongkai Li, Tom Y.-H. Wu, Bishnu P. Nayak, Manmohan Singh, Elena Caproni, Derek T. O'Hagan |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
Science translational medicine. 6(263) |
| ISSN: |
1946-6242 |
| Popis: |
Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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