Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity
| Autor: | Mallesh Beesu, Diptesh Sil, Sunil A. David, Umeharu Ohto, Mihiri S. Weerasinghe, Karishma K. Khetani, Giuseppe Caruso, Toshiyuki Shimizu, H. Tanji, Alex C. D. Salyer |
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| Rok vydání: | 2015 |
| Předmět: |
Agonist
Protein Conformation Stereochemistry medicine.drug_class Drug Evaluation Preclinical Adaptive Immunity Crystallography X-Ray Article Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Adjuvants Immunologic Adjuvanticity Drug Discovery medicine Animals Humans Structure–activity relationship Binding site Receptor 030304 developmental biology 0303 health sciences Chemistry TLR7 Acquired immune system 3. Good health Cell biology Ectodomain Toll-Like Receptor 8 030220 oncology & carcinogenesis Quinolines Molecular Medicine Female Rabbits |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b01087 |
| Popis: | Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼ 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. |
| Databáze: | OpenAIRE |
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