A New Therapeutic Strategy for Asthma:  Inhibition of Cortisol
Metabolism in the Lung

11b-hydroxysteroid dehydrogenase 2 (11b-HSD2) is the enzyme responsible
for conversion of the anti-inflammatory hormone cortisol to cortisone
in the lung and kidney, thus inactivating glucocorticoid response in
these tissues. We propose to develop the first potent and selective
small-molecule inhibitor of 11b-HSD2 as a potential new therapy for
asthma.  Our hypothesis is that inhibition of 11b-HSD2 in the lung will
prevent conversion of the anti-inflammatory steroid cortisol to
inactive cortisone in the lung epithelium, resulting in reduced
bronchial tube swelling associated with asthma attacks.  Vastly
different levels of 11b-HSD2 are expressed in the lung compared to
other organs, providing an avenue for potent inhibition in the lung
without significant inhibition systemically.  Interestingly, a
steroidal natural product isolated from licorice, glycyrrizic acid, has
been used to treat asthma since the 16th century and is a potent
inhibitor of 11b-HSD2.  Glycyrrizic acid binds to the steroid binding
site of 11b-HSD2 which is common to several cortisol/cortisone
metabolizing enzymes and is thus pleiotropic in its effects.  We
propose to generate inhibitors of 11b-HSD2 which bind to the NAD+
binding pocket to achieve highly specific and tight binding inhibitors.
In support of this approach, our laboratory has discovered a potent
and selective NADPH competitive inhibitor of carbonyl reductase 1, an
enzyme in the short-chain dehydrogenase reductase family which includes
11b-HSD2.  Using this inhibitor as a lead structure, we propose
synthesize analogs which are specific for 11b-HSD2 as a potential
alternative or adjunct to synthetic corticosteroid treatment for
asthma.

Kevan Shokat, Ph.D.