Secretory phospholipases A2 (sPLA2) are inflammatory proteins known to play a role in the pathogenesis of many inflammatory diseases. They are a subfamily of PLA2
enzymes that catalyze the hydrolysis of phospholipids, yielding
precursors of pro-inflammatory lipid mediators including bioactive
eicosanoids and platelet-activating factor (PAF). sPLA2 inhibitors hold an established role in inflammation treatment, since inhibition of sPLA2
would in theory prevent the formation of inflammatory eicosanoids prior
to the cyclooxygenase (COX) reaction. To date, the complexity of these
proteins has made it a challenge to develop a successful class of sPLA2 inhibitors, although new approaches open the possibility of future success.
The development of sPLA2 inhibitors as potential
anti-inflammatory agents has been extensively pursued since the release
of arachidonic acid from membrane phospholipids by PLA2 is one of the rate-limiting factors for eicosanoid production. In addition to the production of eicosanoids, PLA2-catalyzed
membrane phospholipid hydrolysis is also the initiating step in the
generation of PAF, a potent inflammatory agent. Thus, inhibition of PLA2
activity should, in theory, be a more effective anti-inflammatory
approach. Furthermore, one of the pathways through which corticosteroids
are suspected of exerting their anti-inflammatory effects is through
sPLA2 inhibition via lipocortin induction. However,
developing an inhibitor that would be selective for the production of
inflammatory metabolites and not inhibit the beneficial properties of
PLA2 has so far proved to be elusive.
Inhibition of specific PLA2 isoforms is potentially an
effective therapy for several inflammatory conditions and has been
actively explored for several years. Despite this, there are no
selective PLA2 inhibitors clinically available to date. The identification and characterization of additional members of the expanding PLA2 family and development of more selective PLA2 inhibitors has not served to elucidate a clinically effective anti-inflammatory role for PLA2 inhibition as was previously hoped. The development of a cell-impermeable sPLA2 inhibitor that would protect the cell membrane from sPLA2 activity without affecting vital intracellular PLA2 activity was proposed to be an effective therapeutic avenue several years ago, but has not borne fruit.
As a recognized target of inflammation research, sPLA2 has
resulted in several failed approaches in trials conducted by the
pharmaceutical industry. For example, Eli Lilly & Co. has conducted
analyses of LY315920NA/S-5920, a selective inhibitor of sPLA2
subtype IIA, to address inflammation related to asthma, arthritis, and
sepsis. In a previous study, LY315920NA/S-5920 was well-tolerated and
appeared to improve survival in a subgroup of patients who received the
drug within 24 hours of first sepsis-induced organ failure.
A subsequent Lilly study was designed to determine whether improvement
in survival could be confirmed in a larger patient population meeting
the characteristics of that subgroup. The study was terminated after
data on 250 patients—with at least two sepsis-induced organ
failures—suggested a significant improvement in 28-day all-cause
mortality would not be found if the trial continued as planned. The
mortality rate was 39.4 percent in the LY315920NA/S-5920 group, compared
with 31.9 percent in the placebo group (p = .092). Additionally, Anthera Pharmaceuticals studied sPLA2 inhibition for acute coronary syndrome also using LY315920NA/S-5920, but the trial failed in Phase III.
A separate research program, conducted by Wyeth Pharmaceuticals,
focused on inflammation associated with the central nervous system and
arthritis. The program was terminated when it was found that the
compound being tested was inhibiting the cPLA2 family, a cousin to sPLA2 that is homeostatic and vital to the cell.
It is vital to inhibit the correct sPLA2 isomers, of which
there are approximately 12, not just one or two most ubiquitous ones. It
is also important not to interfere with the cPLA2 family. A
novel group of compounds called Multi-Functional Anti-Inflammatory Drugs
(MFAIDs) have been rationally designed and synthesized to overcome
these two critical problems and represent not just a single molecule but
an entire new genus of compounds, each different but with a similar
mechanism of action. MFAIDs might offer effective treatment for a wide
range of inflammatory diseases including conditions with pulmonary
inflammation like cystic fibrosis, inflammatory skin diseases such as
eczema, inflammatory bowel disease, and ophthalmic inflammatory
conditions such as conjunctivitis and dry eye. To date, MFAIDs have
shown in vitro and in vivo efficacy in numerous models and patients.
As more information becomes available regarding the role of PLA2 isoforms—including sPLA2—in
different cells and tissues, the medical community looks forward to
developing additional enhanced selective inhibitors. For example, as
more information becomes available concerning the structure, functional
sites and modulators of activity, selective sPLA2 inhibitors
might be developed to specifically target functional groups on the
enzyme other than the catalytic site or to target alternative
intracellular sites. Additionally, studies that demonstrate inhibition
of sPLA2 activity under experimental conditions might identify alternative avenues to explore for therapeutically suitable sPLA2 inhibitors.
The continuing study of sPLA2 as a target of inflammation research is bound to inspire innovation in the years to come.