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


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)-?-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-?-induced ISRE activation signal. These conditions were confirmed in an initial pilot screen, followed by the main screen for evaluating prolongation of an IFN-?-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 receptor 4 agonist, lipopolysaccharide, as an adjuvant. Selected compounds significantly augmented antigen-specific immunoglobulin responses.

SUBMITTER: Shukla NM 

PROVIDER: S-EPMC6697428 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Shukla Nikunj M NM   Arimoto Kei-Ichiro KI   Yao Shiyin S   Fan Jun-Bao JB   Zhang Yue Y   Sato-Kaneko Fumi F   Lao Fitzgerald S FS   Hosoya Tadashi T   Messer Karen K   Pu Minya M   Cottam Howard B HB   Carson Dennis A DA   Hayashi Tomoko T   Zhang Dong-Er DE   Corr Maripat M  

SLAS discovery : advancing life sciences R & D 20180511 9


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 t  ...[more]

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