Download Document 8652298

VIPER A virally-­‐derived pep-de that blocks inflamma-on Overview Toll-­‐like receptor 4 (TLR4) recognises pathogens leading to ac8va8on 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. Over millennia, viruses have op8mised their ability to inhibit the immune response. Thus the Vaccinia virus protein A46 displays a remarkable ability to inhibit TLR4 func8on. We have exploited this viral know-­‐how and developed an 11-­‐amino acid pep8de from A46, termed VIPER, which, when fused to a cell-­‐penetra8ng delivery sequence, potently and specifically inhibits TLR4-­‐mediated responses in vitro and in vivo. Advantages Possible Applica1ons VIPER most likely represents a surface of A46 that has been op8mised by the virus to potently inhibit TLR4, so has already been through a ‘naturally occurring drug development programme’. VIPER is more effec8ve at inhibi8ng TLR4 than other currently used pep8de inhibitors of TLR4, in that it is more specific, more potent, less toxic, and is effec8ve in primary human cells. Experimental tool for exploring TLR4 complex forma8on and signalling, for analysing the role of TLR4 in in vivo models of disease andfor predic8ng a role for Mal or TRAM in a disease process. Development as a therapeu8c agent, for example by developing it into a pep8domime8c. Analysis of surfaces on Mal and TRAM targeted by VIPER as drugable sites during inflamma8on. Market Therapeu8cs: Synthesis, Formula8on, Processing and Drug Delivery VIPER inhibits TLR4 in primary
human blood cells.
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.
IP Status US Patent granted EP Patent pending US13/129657 Structural model of A46 showing position of VIPER in the protein.
VIPER is a potent inhibitor of
TLR4-mediated TNF production.
When blood cells were treated with
a range of VIPER concentrations,
dose-dependent inhibition of TLR4induced TNF was observed, giving
an IC50 of 5 µM. The production of
other TLR4-dependent cytokines
was also blocked.
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 posiFon of VIPER on the protein’s surface (purple). Further worked showed that VIPER targeMed the TLR4 components Mal (D) and TRAM (E). VIPER appears on an electroposiFve patch on A46 (C, blue), likely allowing a complementary interacFon with the electronegaFve (red) surfaces of Mal (D) and TRAM (E). EP09760327.8 Opportunity Research collabora8on, Available to license
Technology and Patent Status VIPER is has been validated preclinically for efficacy, with ongoing work being carried out in disease models. . US patent 8,722,052 has been granted and European patent EP2362782A1 is pending Researcher(s) Prof Andrew Bowie 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.
The opportunity Contact VIPER is available for immediate license. Work is ongoing to develop VIPER into Mal-­‐ and TRAM-­‐specific inhibitors, and also to further inves8gate its in vivo efficacy in disease models. Sample products are available on request. Further technical informa8on on VIPER can be found in Lysakova-­‐Devine et al (2010) J. Immunol. 185: 4261-­‐4271. IRC
Dr. Emily Vereker, Case Manager, Life Sciences [email protected] +353 1 896 4152 Reference: AB01-­‐108-­‐01