Biology Reference
In-Depth Information
The GAF-Tandem Domain of Phosphodiesterase
5 as a Potential Drug Target
Joachim E. Schultz, Torsten Dunkern, Elvira Gawlitta-Gorka,
and Gabriele Sorg
Contents
1 Introduction and Scope . . . ...................................................................... 152
2 Requirements to Run a High-Throughput Screen ............................................ 154
3 Running a High-Throughput Screen for the hPDE5 Tandem
GAF Domain as a Drug Target ................................................................ 157
4 Evaluation and Retest of Hits .................................................................. 158
5 Hit Confirmation Using Assays with Human PDE5 ......................................... 161
6 Conclusions and Outlook . ...................................................................... 163
References . . . .........................................................................................164
Abstract Classic PDE5 inhibitors interact with and block the catalytic site of
PDE5. They have been clinically validated for treatment of erectile dysfunction
as well as reduction of pulmonary arterial pressure, improvement of exercise
capacity, quality of life, and arterial oxygenation in patients with secondary pulmo-
nary hypertension. Minor side effects are visual disturbances, headache, migraine,
back pain, and interaction with nitrates (hypotension). Some of those side effects
presumably can be ameliorated by improving selectivity and pharmacokinetics;
other side effects probably are target related due to inhibition of basic physiological
processes. Target related side effects may be bypassed by using PDE5 inhibitors
with a different mode of action: PDE5, like PDE2, PDE6, PDE10, and PDE11, is a
multidomain protein with an N-terminal tandem GAF domain, which in case of
PDE5, is allosterically activated by cGMP. Potential inhibitors acting at the PDE5
GAF domain would be expected to inhibit only pathophysiologically upregulated
PDE5 activity, whereas basal activity of PDE5 would remain unaffected.
J.E. Schultz (
*
)
Pharmazeutisches Institut der Universitat Tubingen, Auf der Morgenstelle 8, 72076 Tubingen,
Germany
e-mail: joachim.schultz@uni-tuebingen.de
T. Dunkern, E. Gawlitta-Gorka, and G. Sorg
Nycomed GmbH, Byk-Guldenstr. 2, 78467 Constance, Germany
e-mail: gabriele.sorg@nycomed.com
