Download VIPER: a virally-derived peptide that blocks inflammation Overview Possible Applications

VIPER: a virally-derived peptide that
blocks inflammation
Overview
Possible Applications
Toll-like receptor 4 (TLR4) recognises pathogens leading to
activation of the immune response, but also contributes to the
development of a number of autoimmune and inflammatory
diseases. As such, it has become a new target for drug development.
Experimental tool for exploring TLR4 complex formation and
signalling, for analysing the role of TLR4 in in vivo models of
disease andfor predicting a role for Mal or TRAM in a
disease process.
Over millennia, viruses have optimised their ability to inhibit the
immune response. Thus the Vaccinia virus protein A46 displays a
remarkable ability to inhibit TLR4 function.
Development as a therapeutic agent, for example by
developing it into a peptidomimetic.
We have exploited this viral know-how and developed an 11-amino
acid peptide from A46, termed VIPER, which, when fused to a cellpenetrating delivery sequence, potently and specifically inhibits
TLR4-mediated responses in vitro and in vivo.
Analysis of surfaces on Mal and TRAM targeted by VIPER as
drugable sites during inflammation.
Advantages
VIPER most likely represents a surface of A46 that has been
optimised by the virus to potently inhibit TLR4, so has already been
through a ‘naturally occurring drug development programme’.
VIPER is more effective at inhibiting TLR4 than other currently
used peptide inhibitors of TLR4, in that it is more specific, more
potent, less toxic, and is effective in primary human cells.
Structural model of A46 showing position of VIPER in the protein.
VIPER inhibits TLR4 in primary human
blood cells.
A46 was aligned with B14 and A52 (A), which have known crystal structures. This allowed a
model of A46 to be generated (B), showing the position of VIPER on the protein’s surface
(purple). Further worked showed that VIPER targetted the TLR4 components Mal (D) and
TRAM (E). VIPER appears on an electropositive patch on A46 (C, blue), likely allowing a
complementary interaction with the electronegative (red) surfaces of Mal (D) and TRAM (E).
TNF is produced when cells are stimulated
with LPS, a TLR4 agonist. Pretreatment of
cells with VIPER, but not another TLR
inhibitory peptide, P13, blocked TNF
production from human cells. TNF, a
cytokine, is a well known mediator of
inflammation.
Technology and Patent Status
VIPER is a potent inhibitor of TLR4mediated TNF production.
VIPER is at the product development stage.
When blood cells were treated with a range
of VIPER concentrations, dose-dependent
inhibition of TLR4-induced TNF was
observed, giving an IC50 of 5 µM. The
production of other TLR4-dependent
cytokines was also blocked.
PCT application E2009/000080 has been nationalised in the
following countries: US, Europe & Canada
The opportunity
VIPER is available for immediate license.
VIPER inhibitsTLR4-induced cytokine
secretion in vivo.
When mice were injected with VIPER and
LPS, reduced cytokine production in the
serum was observed, compared to
injection with LPS and a control peptide.
Work is ongoing to develop VIPER into Mal- and TRAM-specific
inhibitors, and also to further investigate its in vivo efficacy in
disease models.
Sample products are available on request.
Further technical information on VIPER can be found in
Lysakova-Devine et al (2010) J. Immunol. 185: 4261-4271.
Researcher:
Contact:
Ref:
Prof. Andrew Bowie
Dr. Emily Vereker, TTO Case Manager [email protected]
AB01-108-01
+ 353 1 896 4152
IRC