Genomic-based high throughput screening identifies small molecules that differentially inhibit the antiviral and immunomodulatory effects of IFN-α.

Topics: Gene expression, Systemic lupus erythematosus, Cell nucleus Pages: 9 (6303 words) Published: April 17, 2014
Genomic-Based High Throughput Screening Identifies Small
Molecules That Differentially Inhibit the Antiviral and
Immunomodulatory Effects of IFN-α
Bo Chen,1* Qin Zong,2* Ricardo Cibotti,1* Chad Morris,1 Juana Castaneda,2 Brian Naiman,1 Derong Liu,2 Anna Glodek,2 Gary P Sims,1 Ronald Herbst,1 Stephen K Horrigan,2 Peter A Kiener,1 Dan Soppet,2 Anthony J Coyle,1 and Laurent Audoly1

1

Respiratory, Inflammation and Autoimmunity Department, MedImmune Inc., Gaithersburg, Maryland, United States of America; Avalon Pharmaceuticals Inc., Germantown, Germantown, Maryland, United States of America

2

Multiple lines of evidence suggest that inhibition of Type I Interferons, including IFN-α, may provide a therapeutic benefit for autoimmune diseases. Using a chemical genomics approach integrated with cellular and in vivo assays, we screened a small compound library to identify modulators of IFN-α biological effects. A genomic fingerprint was developed from both ex vivo patient genomic information and in vitro gene modulation from IFN-α cell-based stimulation. A high throughput genomic-based screen then was applied to prioritize 268 small molecule inhibitors targeting 41 different intracellular signaling pathways. Active compounds were profiled further for their ability to inhibit the activation and differentiation of human monocytes using disease-related stimuli. Inhibitors targeting NF-κB or Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling emerged as “dissociated inhibitors” because they did not modulate IFN-α anti-viral effects against HSV-1 but potently inhibited other immune-related functions. This work describes a novel strategy to identify small molecule inhibitors for the treatment of autoimmune disorders. Online address: http://www.molmed.org

doi: 10.2119/2008-00028.Chen

INTRODUCTION
Systemic Lupus Erythematosus (SLE)
is a prototypic systemic autoimmune disorder that is characterized by anti-nuclear autoantibodies and the presence of inflammatory lesions targeting a variety of tissues including the skin, joints, brain,

heart, lung, and kidney (1). Development
of the disease can lead to deposition of
immune complexes in the kidney, renal
failure, and death. SLE is diagnosed
mostly in woman during childbearing
years and affects approximately five million people worldwide. Therapies have remained essentially unchanged for over
20 years and still rely largely on undesirable long term use of corticosteroids and

immunosuppressive drugs to slow disease
progression. The need for safe, new, effective therapies is urgently required. Recently, it has emerged that type I Interferons (IFN) play a prominent role in the pathogenesis of lupus, however, type I

IFNs also play an important role in host
defense against viral infection (2). Therefore, we are faced with the challenge of developing a screening strategy that identifies drugs that inhibit the pro-inflammatory
response of type I IFNs while retaining
protection from viral infection.
Type I IFNs are a family of pleiotropic
cytokines that play an important role in
modulating nearly all phases of immune
and inflammatory responses (2,3). Type I

*BC, QZ, and RC contributed equally to this work.
Address correspondence and reprint requests to Anthony J Coyle, One Medimmune Way, Gaithersburg, MD 20878. Phone: 301-398-4520; Fax: 301-398-9520; E-mail: Coylea@ medimmune.com.
Submitted March 5, 2008; Accepted for publication April 30 2008; Epub (www.molmed. org) ahead of print May 5, 2008.

3 7 4 | C H E N E T A L . | M O L M E D 1 4 ( 7 - 8 ) 3 7 4 - 3 8 2 , J U LY- A U G U S T 2 0 0 8

IFNs include 13 functional IFN-α genes,
and single IFN-β, IFN-ε, IFN-κ, and IFN-ω
genes (3). Binding of type I IFNs to a
common receptor (IFNAR) composed of
a unique IFNAR1 subunit and a functionally active IFNAR2c subunit, results in the activation of JAK1 and TYK2 kinases that subsequently activate the signal transducer and activator...


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