Human
tryptase is a structurally unique and mast cell specific
trypsin-like serine protease. Recent
biological and immunological investigations have implicated
tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including
rhinitis,
conjunctivitis, and most notably
asthma. A growing body of data further implicates
tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective
tryptase inhibitors, though, has facilitated the validation of this
protease as an important therapeutic target as well. Herein, we describe the design and potency of four classes of selective
tryptase inhibitors, of which the first three types are synthetic and the fourth is natural in origin: 1) peptidic inhibitors (e.g.,
APC-366), 2) dibasic inhibitors (i.e.,
pentamidine-like), 3) Zn(2+)-mediated inhibitors (i.e.,
BABIM-like), and 4)
heparin antagonists (e.g.,
lactoferrin). These inhibitors have been tested in the airways and skin of allergic sheep.
Aerosol administration of
tryptase inhibitors from each structural class 30 minutes before, and 4 hours and 24 hours after
allergen challenge, abolishes late phase bronchoconstriction and
airway hyperresponsiveness in a dose-dependent manner. Moreover,
intradermal injection of
APC-366 blocks the cutaneous response to
antigen. These studies provide the essential proof-of-concept for the further pursuit of
tryptase inhibitors for the treatment of
asthma, and perhaps other allergic diseases. Results from clinical studies with the first generation
tryptase inhibitor
APC-366, currently in phase II trials for the treatment of
asthma, provide additional support for a pathological role for
tryptase in this disease. Notable advances in the area of
tryptase inhibitor design at Axys
Pharmaceuticals, Inc. include a novel,
zinc-mediated,
serine protease inhibitor technology (described herein), and the discovery of a unique class of extremely potent and selective dibasic
tryptase inhibitors. Independently, an X-ray crystal structure of active
tryptase tetramer complexed with 4-amidinophenyl
pyruvic acid has been reported. It is anticipated that these discoveries will further accelerate the design of structurally novel
tryptase inhibitors as well as the development of new drugs for the treatment of
mast cell tryptase-mediated disorders.