Identification of Compounds That Prolong Type I Interferon Signaling as Potential Vaccine Adjuvants

SLAS Discovery
Nikunj M ShuklaMaripat Corr

Abstract

Vaccines are reliant on adjuvants to enhance the immune stimulus, and type I interferons (IFNs) have been shown to be beneficial in augmenting this response. We were interested in identifying compounds that would sustain activation of an endogenous type I IFN response as a co-adjuvant. We began with generation of a human monocytic THP-1 cell line with an IFN-stimulated response element (ISRE)-β-lactamase reporter construct for high-throughput screening. Pilot studies were performed to optimize the parameters and conditions for this cell-based Förster resonance energy transfer (FRET) reporter assay for sustaining an IFN-α-induced ISRE activation signal. These conditions were confirmed in an initial pilot screen, followed by the main screen for evaluating prolongation of an IFN-α-induced ISRE activation signal at 16 h. Hit compounds were identified using a structure enrichment strategy based on chemoinformatic clustering and a naïve "Top X" approach. A select list of confirmed hits was then evaluated for toxicity and the ability to sustain IFN activity by gene and protein expression. Finally, for proof of concept, a panel of compounds was used to immunize mice as co-adjuvant with a model antigen and an IFN-inducing Toll-like rece...Continue Reading

References

Aug 1, 1995·Proceedings of the National Academy of Sciences of the United States of America·O BoussifJ P Behr
Jan 1, 1995·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·G UzéK E Mogensen
Feb 29, 1996·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·J BriscoeI M Kerr
Jul 19, 1996·Journal of Medicinal Chemistry·G W Bemis, M A Murcko
Jan 15, 2002·The Journal of Biological Chemistry·Michael P MalakhovDong-Er Zhang
Jun 22, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Enrico ProiettiFilippo Belardelli
Sep 19, 2006·Immunity·Anette H H van Boxel-DezaireGeorge R Stark
Jul 17, 2008·Expert Opinion on Pharmacotherapy·Kristen O'Dwyer, Peter Maslak
Oct 23, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jung-Hwan KimDong-Er Zhang
May 19, 2009·Bioconjugate Chemistry·Michael ChanDennis A Carson
Apr 30, 2010·Journal of Chemical Information and Modeling·David Rogers, Mathew Hahn
Apr 22, 2011·Expert Review of Vaccines·Derek T O'HaganGiuseppe Del Giudice
May 18, 2011·Nucleic Acids Research·Tyler W H BackmanThomas Girke
Aug 20, 2011·European Journal of Medicinal Chemistry·Asal Fallah-TaftiAbbas Shafiee
Dec 7, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aurangzeb HasanMuhammed Nadeem Akhtar
Jul 6, 2012·Statistics in Medicine·Minya PuKaren Messer
May 10, 2013·Journal of Medicinal Chemistry·Michael ChanHoward B Cottam
Jul 19, 2013·Journal of Biomolecular Screening·Dhara A PatelMichael J Holtzman
Apr 19, 2016·Immunological Reviews·Georg GasteigerWolfgang Kastenmüller
Feb 7, 2017·Nature Structural & Molecular Biology·Kei-Ichiro ArimotoDong-Er Zhang

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Citations

Nov 9, 2018·BioMed Research International·Fumi Sato-KanekoTomoko Hayashi

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Methods Mentioned

BETA
flow cytometry
Assay
transfection
electrophoresis
Fluorescence
enzyme-linked immunosorbent assay
fluorescence-activated cell sorting
FRET
ELISA

Software Mentioned

ChemMine
GraphPad
Chem3D
Prism

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