As life expectancy increases, the need for effective remedies against cognitive decline emerges. Worldwide, 44 million people are affected by dementia, and this number is predicted to triple by 2050. Approved drugs target acetylcholinesterase and N-methyl-D-aspartate receptors, but limited efficacy is reported against Alzheimer’s disease (Lane et al. Eur J Neurol 2018, doi.org/10.1111/ene.13439). Although, neuroprotection and cognitive enhancement are associated with increased 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP) levels in brain, that result from the inhibition of phosphodiesterases (PDEs). PDE5 and PDE9 are cGMP-selective enzymes attracting attention as potential targets to modulate signal transduction by regulating cAMP and/or cGMP, thus mediating neurotransmitter release, amelioration of microvascular dysfunction and neuronal plasticity (Bender et al. Pharmacol Rev 2006, doi.org/10.1124/pr.58.3.5; Ribaudo et al. ACS Chem. Neurosci. 2020, doi.org/10.1021/acschemneuro.0c00244). In this contribution, the discovery of isoform-selective inhibitors is described, based on PDE9 features that encourage the development of neuroprotective agents targeting this enzyme: its expression in the brain, the presence within its structure of a peculiar accessory pocket, the asymmetry between the two subunits composing the dimer, and the selectivity for chiral species (Rosenbrock et al. J Pharmacol Exp Ther 2019, doi.org/10.1124/jpet.119.260059). In this context, the world of natural compounds represents a source of variegated and asymmetric structures (Ribaudo et al. Pharmaceuticals 2021, doi.org/10.3390/ph14010058). We report the isolation and characterization of scaffolds from natural sources, and the computational studies that guided the preparation of semi-synthetic drug-like derivatives with improved affinity for PDEs (Ribaudo et al. Natural Product Research 2017, doi.org/10.1080/14786419.2016.1269101; Oselladore et al. New J. Chem. 2020, doi.org/10.1039/D0NJ02537B; Ribaudo et al. Fitoterapia 2015, doi.org/10.1016/j.fitote.2015.06.020). Additionally, we describe the development of a cell-free ligand screening protocol based on mass spectrometry that allows to detect noncovalent ligand-target interaction rapidly and quantitatively, thus accelerating hit identification and optimization.

Computer-aided and mass spectrometry-based screening of CNS-targeting phosphodiesterase 9 inhibitors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.