Abstract
Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response.
Highlights
Phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of a phosphodiester bond, most notably those of the second messenger cascade molecules cyclic adenosine monophosphate and cyclic guanosine monophosphate. cAMP and cGMP bind to the regulatory units of protein kinase A(PKA) allowing for phosphorylation transducing signal cascades in the cell [1,2,3]
PDE enzymes have remained an interest within the pharmaceutical industry, as inhibition of PDE can increase the levels of cAMP or cGMP enhancing or prolonging their natural physiological effects [5]
It has been known for years that increased cAMP from PDE4 inhibition or gene knockout were able to markedly decrease inflammatory responses in immune cells [26]. cAMP controls inflammation through several distinct pathways, including cyclic nucleotide-gated ion channels, cAMP-activated protein kinases (PKA), or exchange proteins directly activated by cAMP (Epac) [27]
Summary
Phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of a phosphodiester bond, most notably those of the second messenger cascade molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). cAMP and cGMP bind to the regulatory units of protein kinase A(PKA) allowing for phosphorylation transducing signal cascades in the cell [1,2,3]. Various small molecular compounds have been discovered to inhibit PDEs. For example, caffeine, aminophylline, and IBMX are nonselective PDE inhibitors [6] that increase intracellular cAMP, thereby activating PKA, inhibiting tumor necrosis factor (TNF) and other inflammatory cytokines, and reducing inflammation [7]. We sought to better understand Forsythia lignan Forsythin structure-function relationships and it was used to design and test a new class of selective PDE4 inhibitors. These selective PDE4 inhibitors exert potent antiinflammatory activity in several murine models of inflammation
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