Inhibitors of Signal Peptide Peptidase for Anti-Viral Therapy

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The objectives of this application are to perform mechanistic studies on proteolysis by signal
peptide peptidase (SPP) and to develop assays for identifying inhibitors of the protease.
Inhibitors of SPP activity could have potential as novel drug candidates for treatment of
hepatitis C virus (HCV) and for targeting immunoevasins encoded by viruses, such as US2,
which is encoded by human cytomegalovirus (HCMV).
HCV
Globally, approximately 130 million individuals have been infected with HCV. In the UK, HCV
infection has been diagnosed in 90,000 individuals but the true figure is closer to 270,000.
Chronic infection is a leading cause of liver disease, accounting for a high proportion of
cirrhosis and hepatocellular carcinoma. Predictions indicate that there will be about a 3-fold
rise in such HCV-associated diseases over the next decade. Current therapies to treat
infection have a 50% success rate, but a large cohort of patients fails to respond. Hence,
improved treatments are needed to reduce the future disease burden. In a landmark study,
we established that SPP, a cellular intramembrane-cleaving protease (I-CLiP), is essential for
maturation of HCV core (capsid) protein. Based on these data, a patent application claiming
SPP as a target for HCV was filed by MRCT, since SPP inhibitors would offer a novel approach
for intervention in HCV infection. Pharmaceutical companies have expressed interest in SPP,
but none has committed to this area, primarily due to 1) the absence of a robust assay and
2) the lack of proof of concept studies as HCV could not be cultivated under laboratory
conditions. From unpublished studies, we have now demonstrated that SPP cleavage of core
is needed for production of infectious HCV. Having established proof of principle, the
considered view is that the combination of our existing IP position along with development of
a robust assay for screening compound libraries would place MRC in a strong position for
translational opportunities. Between 2005-2007, a feasibility study to investigate difficulties
with development of SPP assays was undertaken with MRCT and they remain convinced of
the potential for therapeutic development.
HCMV
HCMV, a member of the Betaherpesvirinae family, infects between 60-90% of the world
population, typically establishing a latent infection. It is the most common cause of
congenital infection in humans and is particularly problematic in transplant recipients and
HIV-infected persons. To evade host immune defence systems, the virus encodes a suite of
immunoevasins that perturb antigen presentation. HCMV US2 is responsible for degradation
of MHC class I molecules by interacting with SPP although the mechanisms involved are not
known. Utilising the extensive knowledge and experience gained from studies on SPP
maturation of HCV core, there is an opportunity to expand MRC interests to investigate
whether SPP inhibitors may have an impact on immune recognition in HCMV infection.
Section 3: Description of Proposed Project (~800 words)
3.1 Scientific Background
Considerable effort is being devoted to develop compounds which target HCV functions but
development of resistance is acknowledged as a problem. A broader range of targets,
including cellular functions, is preferred to widen the availability of anti-viral therapies. Apart
from virus-encoded functions, few cellular factors are known to be essential for virus
propagation. Our interests in SPP date from 2000 when we established that HCV core protein
required SPP for maturation (McLauchlan et al., 2002, EMBO J 21, 3980-3988). Since it was
not possible to cultivate HCV in the laboratory, we tested the effect of blocking core
maturation by SPP in tamarins using GB virus-B (GBV-B), a close genetic relative to HCV, as
a surrogate model. Infection in animals was attenuated when SPP proteolysis of GBV-B core
was impaired (Targett-Adams et al., 2006, J Biol Chem 281, 29221-29227). Our
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