title: Novel PDE4 inhibitors derived from Chinese medicine forsythia.
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.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Alison C
authors.initials: AC
authors.lastname: McKelvey
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Nate M
authors.initials: NM
authors.lastname: Weathington
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Rahel L
authors.initials: RL
authors.lastname: Birru
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Travis
authors.initials: T
authors.lastname: Lear
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
mesh_terms: D000818:Animals; D003198:Computer Simulation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D031657:Forsythia / Q000737:chemistry*; D007249:Inflammation / Q000188:drug therapy; D008031:Lignin / Q000302:isolation & purification / Q000494:pharmacology*; D055370:Lung Injury / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology / Q000627:therapeutic use; D010946:Plants, Medicinal / Q000737:chemistry; D012772:Shock, Septic / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D008031:Lignin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4