Design of Phosphodiesterase 4D (PDE4D) Allosteric Modulators for Enhancing Cognition with Improved Safety

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2009 Dec 29

PMID 20037581

Citations 134

Authors

Alex B Burgin

Olafur T Magnusson

Jasbir Singh

Pam Witte

Bart L Staker

Jon M Bjornsson

Margret Thorsteinsdottir

Sigrun Hrafnsdottir

Timothy Hagen

Alex S Kiselyov

Lance J Stewart

Mark E Gurney

Affiliations

Soon will be listed here.

Abstract

Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

Citing Articles

Molecular Properties of Phosphodiesterase 4 and Its Inhibition by Roflumilast and Cilomilast.

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PMID: 39942796 PMC: 11820465. DOI: 10.3390/molecules30030692.

PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review.

Kumar R, Khan M, Panwar A, Vashist B, Rai S, Kumar A Open Respir Med J. 2025; 18():e18743064340418.

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Topical Application of Dipyridamole and Roflumilast Combination Nanoparticles Loaded Nanoemulgel for the Treatment of Psoriasis in Rats.

Maded Z, Lassoued M, Taqa G, Fawzi H, Abdulqader A, Jabir M Int J Nanomedicine. 2024; 19:13113-13134.

PMID: 39679247 PMC: 11638079. DOI: 10.2147/IJN.S492180.

PDE4D: A Multipurpose Pharmacological Target.

Lusardi M, Rapetti F, Spallarossa A, Brullo C Int J Mol Sci. 2024; 25(15).

PMID: 39125619 PMC: 11311937. DOI: 10.3390/ijms25158052.

Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.

Staller D, Bennett R, Mahato R Expert Opin Ther Targets. 2024; 28(7):545-573.

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