Molecular Determinants of GS-9620-Dependent TLR7 Activation

PloS One
Indrani RebbapragadaStefan Pflanz

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...Continue Reading

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Citations

Feb 11, 2018·Liver International : Official Journal of the International Association for the Study of the Liver·Raymond F SchinaziTarik Asselah
Nov 5, 2019·Frontiers in Immunology·Amanda B MacedoAlberto Bosque
Oct 27, 2016·Current Opinion in Infectious Diseases·Jiaqian PanJing Tang
Apr 13, 2019·Archivum Immunologiae Et Therapiae Experimentalis·Jan ŻeromskiIwona Mozer-Lisewska
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Mar 24, 2020·European Journal of Medicinal Chemistry·Cindy PatinoteCarine Deleuze-Masquéfa
Mar 9, 2021·Expert Opinion on Drug Discovery·Xuan HuangMengji Lu
Jun 11, 2021·Journal of Medicinal Chemistry·Arindam TalukdarDipika Sarkar

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Methods Mentioned

BETA
X-ray
ELISA
PCR
size exclusion chromatography
density gradient centrifugation
glycosylation
co-immunoprecipitation
immunoprecipitation
flow cytometry

Software Mentioned

GraphPad Prism
Macromodel
Flo
Jo
Prime

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