1. Molecular Determinants of GS-9620-Dependent TLR7 Activation.
- Author
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Rebbapragada, Indrani, Birkus, Gabriel, Perry, Jason, Xing, Weimei, Kwon, HyockJoo, and Pflanz, Stefan
- Subjects
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TOLL-like receptors , *ORAL drug administration , *HIV-positive persons , *ANTIVIRAL agents , *THERAPEUTICS , *HIV infections , *DRUG efficacy - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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