Abstract
GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands.
Highlights
The Toll-like receptors (TLRs) are a family of pattern-recognition receptors that play a critical role in coordinating both innate and adaptive immune responses towards pathogens [1] [2] [3]
The physiochemical properties of GS-9620 allow the small molecule to rapidly and selectively enter endo-lysosomal compartments where it binds to TLR7 in a pH-sensitive manner
We show evidence to suggest that TLR7 likely stabilizes itself through adopting a homo-dimer conformation independent of ligand, similar to TLR8 and TLR9
Summary
The Toll-like receptors (TLRs) are a family of pattern-recognition receptors that play a critical role in coordinating both innate and adaptive immune responses towards pathogens [1] [2] [3]. TLRs are type I trans-membrane proteins that contain several tandem leucine-rich repeat (LRR) motifs involved in ligand recognition and binding, a trans-membrane domain and a cytoplasmic Toll-IL-1 receptor homology (TIR) domain required for signal transduction [4]. TLR8 and TLR9 were shown to exist as preformed protein dimers, independent of ligand binding, which is in contrast to cell-surface TLRs where ligand binding induces receptor dimerization [9] [10] [11] [12]. Biochemical studies with TLR9 and crystal structures of TLR8 in complex with small molecule agonists indicate
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