Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity |
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| Affiliation: | 1. Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States;2. Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States;3. Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States;4. GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States;1. Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States;2. Biocon-Bristol-Myers Squibb R &D Center (BBRC), Biocon Park, Jigani Link Rd, Banglore 560099, India;3. Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States;1. Department of Zoology and Centre of Advanced Studies in Zoology, Panjab University, Chandigarh 160 014, India;2. Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India;1. Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, CA 92121, USA;2. Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes of Biomedical Research, 4002 Basel, Switzerland;1. Computer-Aided Drug Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Strasse 2+4, 14195 Berlin, Germany |
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| Abstract: | Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased potency for TLR7/8 activity, cytokine induction and DC maturation. |
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| Keywords: | Toll-like-receptor TLR7 TLR8 Oxoadenine |
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