Development of Phosphodiesterase-Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity.

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE-PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE-PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems-cAMP-specific PDE8-PKAR, cGMP-specific PDE5-PKG, and dual-specificity RegA-RD complexes-and ranked inhibitors according to their inhibition potency. Targeting PDE-PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.

Botanical Medicine and Natural Products Used for Erectile Dysfunction.

INTRODUCTION: Erectile dysfunction is the persistent or recurrent inability to achieve or maintain an erection sufficient for intercourse. Despite various treatment options, not all patients respond adequately and their usefulness is limited by adverse effects and cost. Botanical medicine and natural products have been and continue to be invaluable and untapped sources of new drugs, including potentially those to treat erectile dysfunction. OBJECTIVES: To review the current literature on botanical medicine traditionally used as aphrodisiacs and treatment of erectile dysfunction, in particular, scientific and clinical investigations that have been performed, possible active phytoconstituents, and mechanisms of action and to identify gaps in current knowledge to better guide future research efforts. METHODS: A comprehensive literature search was conducted via PubMed, Scopus, Science Direct, and Web of Science on English publications, using various keywords, for example, "herb", "natural product", combined with "erectile dysfunction", "aphrodisiac", and "sexual performance". RESULTS: 369 relevant articles studying medicinal plants used for erectile dysfunction were analyzed. A total of 718 plants from 145 families and 499 genera were reported to be used traditionally as aphrodisiacs and treatment of erectile dysfunction. Top plants used include Pausinystalia johimbe, Lepidium meyenii, and Panax ginseng. Different plant parts are used, with roots being the most common. Less than half of these plants have been evaluated scientifically, using various research methodologies. Clinical trials conducted were collated. Current scientific investigation shows mixed results about their usefulness in enhancing sexual performance. A limited number of studies have attempted to elucidate the mechanisms of action of these medicinal plants. CONCLUSION: A comprehensive literature review on botanical medicine and natural products used for treatment of erectile dysfunction was successfully conducted. Although medicinal plants serve as a potential source of lead compounds for erectile dysfunction drugs, further studies are warranted to further evaluate their efficacy and safety. SinVJ-E, Anand GS, Koh H-L. Botanical Medicine and Natural Products Used for Erectile Dysfunction. Sex Med Rev 2021;9:568-592.