PDE5A x PDE4

On July 9th, 2024, the U.S. FDA approved Arcutis Biotherapeutics' ZORYVE® (roflumilast) for treating atopic dermatitis (AD), the most common type of eczema affecting millions in the U.S. This once-daily, steroid-free cream could become a new standard of care for AD. The approval underscores the growing importance of researching Phosphodiesterase 4 (PDE4) and other PDEs as immunomodulatory targets for various inflammatory diseases. Sino Biological, and its subsidiary SignalChem Biotech, support drug discovery and development targeting PDEs by providing a broad range of PDE families and isoforms. Mechanism of Action Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor that reduces inflammation by increasing cyclic adenosine monophosphate (cAMP) levels, an important molecule in regulating inflammation. PDE4, which breaks down cAMP, has four subtypes (PDE4A, PDE4B, PDE4C, PDE4D) and about 20 isoforms. The anti-inflammatory effects of PDE4 inhibitors are mainly due to inhibiting PDE4B and PDE4D, which are highly expressed in immune cells. By inhibiting these subtypes, roflumilast raises cAMP levels, decreasing pro-inflammatory mediators (e.g., TNF alpha, IL-4, IL-5, IL-13, IL-17A, IL-17F, IL-22) and increasing the anti-inflammatory mediator IL-10. This helps manage inflammatory conditions like atopic dermatitis, alleviating symptoms such as redness, itching, and swelling. PDE4 inhibitors mechanism of action. DOI:10.1517/13543784.2015.1094054 Phosphodiesterases (PDEs) as drug targets PDE enzymes control essential body functions by managing cAMP and cGMP levels. Various PDE inhibitors are developed for diseases: PDE1/2 for cardiovascular and neurological disorders; PDE4 for COPD and atopic dermatitis; PDE5 for erectile dysfunction and pulmonary arterial hypertension; PDE6 for retinal diseases; and PDE7 for inflammatory and autoimmune problems. In summary, PDE inhibitors are powerful tools and hold great promise as drug targets for wide-ranging therapeutic applications. Sino Biological’s Offering to Support Phosphodiesterases (PDEs) Research Sino Biological, along with its subsidiary SignalChem Biotech, is at the forefront of advancing drug development, offering a wide variety of recombinant PDE families and isoforms, to facilitate research on PDEs. Partner with us and visit our website to learn more about how we can best work together to accelerate the PDEs research.

A new mouse study has identified a gene-enzyme interaction that appears to play a key role in how the brain forms memories. The findings provide insights into how PDE inhibitor medications may help diseases like Alzheimer's. The process by which memories are formed in the hippocampus region of the brain is complex. It relies on a precise choreography of interactions between neurons, neurotransmitters, receptors and enzymes. A new mouse study led by researchers at the UC Davis School of Medicine has identified an intricate molecular process involving gene expression in the neurons that appears to play a critical role in memory consolidation. The research was published in Science Signaling. "This is an exciting mechanism. It shows that an enzyme like phosphodiesterase is key in controlling gene expression necessary for memory consolidation," said Yang K. Xiang, a professor in the Department of Pharmacology and senior author of the paper. Xiang's research focuses on understanding how dysregulation or impairment of cellular and molecular mechanisms in the heart and brain can lead to diseases like heart failure and Alzheimer's. Multiple steps in neuron appear critical for memory The new study focuses on the central adrenergic system. The ability to pay attention, which is essential in learning and memory, is controlled by the central adrenergic system in the brain. To understand the components critical for memory, the researchers looked at beta-2 adrenergic receptors. The receptors are present in different cell types throughout the body. They are also found on nerve cells in the hippocampal region of the brain. The researchers show that when beta-2 adrenergic receptors are activated -- through a series of molecular steps known as a signaling pathway -- they stimulate the nucleus of the neuron to export an enzyme, phosphodiesterase 4D5 (PDE4D5). Previous studies have identified PDE4D5 as having a role in promoting learning and memory. Lack of phosphorylation leads to poor memory A crucial step to stimulating this memory-related gene expression -- the export of PDE4D5 -- appears to be the attachment of a phosphate group (known as phosphorylation) to the receptor. This is accomplished by an enzyme known as a kinase. The kinase involved in this case is a G-protein receptor kinase. The researchers used genetically altered mice to test whether phosphorylation of the beta-2 adrenergic receptors by G-protein receptor kinase was necessary for gene expression -- the export of the PDE4D5 enzyme. The mice lacked a phosphorylation site on their beta-2 adrenergic receptors, meaning their neurons could not follow the normal signaling pathway when the receptors were activated. The researchers found that, as expected, these genetically altered mice exhibited poor memory related to space and location. This is the same memory pathway that is disrupted during the early stages of Alzheimer's disease. However, when they provided the memory-impaired mice with a drug known as a PDE4 inhibitor (comparable to the PDE4D5 enzyme that would normally be exported), the mice's ability to learn and retain memories was increased. "The gene expression forms the material foundation of the memory in your brain. If you don't have gene expression, you won't have memory," Xiang explained. PDE inhibitors in Alzheimer's have had mixed results The use of PDE inhibitors is being explored for Alzheimer's disease. Studies of the PDE5 inhibitor sildenafil, known as Viagra, have had mixed results. A 2021 NIH study found Viagra was associated with a reduced risk of Alzheimer's disease, but a later study found Viagra was not associated with lower Alzheimer's risk. "We need to understand what is causing impairment in diseases like Alzheimer's so we can find interventions that allow patients to regain ability or slow down the disease progression," said Xiang. "This study highlights the potential of PDE inhibitors in rescuing memory in Alzheimer's patients." Additional authors on the paper are Joseph M. Martinez, Aleksandra Jovanovicand Josephine de Chabotfrom UC Davis; Ao Shen from UC Davis and Guangzhou Medical University; Bing Xufrom UC Davis and VA Northern California Health Care System; and Jin Zhang from, UC San Diego.