Proteinase inhibitor design
Proteinase inhibitor design is a vital area for both the academic and pharmaceutical communities. This, the sixth, in a highly successful series of symposia, will focus on recent progress in disease-related research
 On Monday 21 April 2008 SCI will host a two-day
symposium on proteinase inhibitor design entitled
‘Proteinase 2008: From Molecules to Medicines.’ This biannual
meeting will be the sixth in a successful series organised
with the RSC. It will focus on recent progress in
the design of inhibitors of proteinases implicated in the
progression of a number of important diseases.
Proteolytic enzymes (proteinases) play crucial roles
in disease progression and in regulating physiological
processes through their role in the degradation of
protein and peptide substrates. The academic community
and pharmaceutical sector have invested considerable
effort in understanding the structure and
function of proteinases to enable the design of effective
therapeutic inhibitors. Significant advances continue
to be made in this area, but drug delivery remains a
considerable challenge. The symposium will cover recent
progress in the design/synthesis of aspartyl, serinyl,
cysteinyl and metallo protease inhibitors for a
diverse range of target indications, and a number of
plenary lectures will provide perspectives on some of
the more successful areas of research in this area.
The first day will be dominated by presentations on
the serine protease inhibitor class. The identification of
dipeptidyl peptidase IV (DPP-IV) as a target for the treatment
of type 2 diabetes led to a race in the industry to
identify inhibitors of this enzyme, culminating in the
recent approval of sitagliptin with other compounds in
late development. Daniel Baeschlin (Novartis) will open
the meeting with a lecture reviewing the DPP-IV area.
The coagulation cascade has been another area of intense
research over recent years, and a lecture from
Wolfgang Haap will discuss his approach to the identification
of inhibitors of Factor Xa, a critical serine protease
in the blood coagulation cascade.
In the antiviral area, Joseph Vacca (Merck) and Montse
Llinas-Brunet (Boehringer Ingelheim) will describe their
work aimed at identifying inhibitors of the Hepatitis C
proteinase, an enzyme essential for the replication of
this highly destructive virus and whose inhibitors have
been shown clinically to prevent viral replication. Miles
Congreve (Astex Therapeutics) will describe work to
identify inhibitors of Urokinase-type plasminogen activator
(uPA), a serine protease involved in tissue remodeling
and cell migration, using the exploitation of Astex’s
fragment-based approach to inhibitor identification.
The introduction of highly active antiretroviral
therapy (HAART) in 1996 dramatically changed the
course of HIV infection and Dale Kempf (Abbott) will
close the first day, switching to the aspartyl protease
inhibitor class. His plenary lecture will reflect on a
decade of work in this area at Abbott that has lead to
the discovery of two HIV protease inhibitors that are
in clinical use today.
The protozoon Plasmodium falciparum is the causative
agent of tropical malaria, which causes significant
human suffering. Among the most interesting antimalarial
target proteins currently being studied are several
proteases including the cysteine proteinases known
as falcipains. Jose Fiandor (GSK) will describe work that
has lead to the identification of falcipain inhibitors as
a potential new antimalarial compound.
Another cysteinyl protease, Cathepsin K, has attracted
much interest owing to its intimate involvement
in bone resorption and has been implicated in
the progression of diseases such as osteoporosis. Several
compounds are now in late development and Urzula
Grabowska will describe Medivirs’ work in this area.
There has been much interest over recent years in
finding inhibitors of the aspartyl protease b-secretase
(BACE) due to its involvement in the formation of beta amyloid,
a key component of amyloid plaques, which
are considered the hallmark of Alzheimer’s disease.
Rainer Machauer (Novartis) will discuss work that has
lead to the identification of orally-active inhibitors of
this important enzyme. The meeting will then switch
to cover metalloprotease inhibitors. Andrew Pape
(AstraZeneca) will discuss inhibiting agrecanases, enzymes
that are now believed to be the principal proteinases
responsible for aggrecan degrdadation and implicated
in osteoarthritis, while Kristina Stenvall
(AstraZeneca) will describe inhibitors of MMP12, an
enzyme that degrades extracellular matrix components,
such as elastin, and as such is involved in tissue
remodelling processes in COPD. Bob Watson (UCB)
will describe work aimed at developing selective
inhibitors of CD23 sheddase from a class of non-selective
MMP inhibitors.
Finally, Klaus Dembowsky (Speedel) will present an
overview of work on renin, a challenging protease target
that has attracted considerable attention over the last two
decades and has recently lead to the approval of aliskiren
as a new treatment for the control of blood pressure.
SCI Fine Chemicals Group
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