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Virology Research Journal
|
Volume 2
Page 44
allied
academies
IMMUNOLOGY AND CELL BIOLOGY
BACTERIOLOGY AND INFECTIOUS DISEASES
&
Global Summit on
Global Congress on
J u n e 2 5 - 2 6 , 2 0 1 8 | A m s t e r d a m , N e t h e r l a n d s
Joint Event on
DISRUPTING THE NFAT-AP-1 TRANSCRIPTIONAL COMPLEX
USING SMALL MOLECULES
Giuliana Mognol
La Jolla Institute for Allergy and Immunology, USA
T
he physical interaction between the transcription factors NFAT and AP-1 is pivotal for both the effector immune response and
for the exacerbated response that happens during autoimmune and inflammatory diseases. In the absence of AP-1, NFAT
directs another programof gene expression, which resembles T cell tolerance, where the cells lose their effector function. We have
screened ~200,000 small drug-like compounds using a FRET assay that allows identifying inhibitors of the NFAT-AP-1 complex
on DNA. We identified 960 candidate inhibitors in the initial screen. 24 compounds were evaluated and one of them actually
inhibits the
in vitro
assembly of the NFAT-AP-1 complex on DNA with no effect on the binding of NFAT or AP-1 individually to their
consensus binding sites. This compound also inhibits the induction of cytokine genes that depend on NFAT-AP-1 interaction, such
as IL2, but not of those regulated independently of NFAT-AP-1 cooperation, such as TNF. The differential effect on IL2 and TNF
gene expression indicates that selective inhibition of NFAT-AP-1 complexes in preference to other NFAT transcriptional complexes
may be achievable by small molecules. One caveat is that further experiments have shown that this compound binds directly to
DNA and not to the interface between NFAT and AP-1 as desired. We are currently developing an ELISA assay to pinpoint inhibitors
that bind at the NFAT-AP-1 interface, and plan to re-test the other 936 compounds identified in the initial high-throughput screen.
A proper inhibitor targeting NFAT-AP-1 complexes might redirect T cell transcription from an effector program to a tolerance
program, and might find practical applications in the treatment of autoimmune and inflammatory diseases.
gmognol@lji.orgVirol Res J 2018, Volume 2