Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity

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• 作者：Mallesh Beesu ; Giuseppe Caruso ; Alex C. D. Salyer ; Karishma K. Khetani ; Diptesh Sil ; Mihiri Weerasinghe ; Hiromi Tanji ; Umeharu Ohto ; Toshiyuki Shimizu ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7833-7849
• 全文大小：898K
• ISSN：1520-4804

文摘

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 鈥渄esigning in鈥?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 鈭?0-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.