title: Selective inhibition of the interaction of C1q with immunoglobulins and the classical pathway of complement activation by steroids and triterpenoids sulfates.
abstract: Since undesirable activation of the complement system through the classical pathway is associated with tissue damage and other pathologic proinflammatory consequences at ischemia/reperfusion injury, autoimmune diseases, and rejection of allo- and xenografts, creation of selective inhibitors of the classical pathway leaving the alternative pathway intact is of great importance. Classical pathway is triggered by binding of its recognizing unit, protein C1q, to a number of targets like antibodies, pentraxins, apoptotic cells, and others. In order to obtain inhibitors blocking the first step of the classical cascade, synthesis of sulfates of steroids (Delta(5)-3beta-hydroxycholenic, Delta(5)-3beta-hydroxyetiocholenic, deoxycholic, and cholic acids) and triterpenoids (betulin, 20,29-dihydro-20,29-dichloromethylenbetulin, betulinic, ursolic, and oleanolic acids) has been performed. Testing of the compounds in classical pathway inhibition assay has displayed derivatives of triterpenoid betulin (betulin disulfate and betulinic acid sulfate) to be the most potent inhibitors. Further studies of the two compounds established that their activity to inhibit the classical pathway had been due to their capability to block the interaction of C1q with antibodies. Betulin disulfate and betulinic acid sulfate have shown weak inhibition of the alternative route of activation, what makes them promising inhibitors for the selective suppression of the classical complement pathway at the earliest possible level as well as perspective agents for blocking the interaction of C1q with its other targets.
authors: M.V. Lomonosov State Academy of Fine Chemical Technology, Biotechnology Department, Vernadskogo str., 86, 119571 Moscow, Russia. sveta407@mail.ru
authors: Svetlana
authors: S
authors: Bureeva
authors: Julian
authors: J
authors: Andia-Pravdivy
authors: Andrey
authors: A
authors: Symon
authors: Anna
authors: A
authors: Bichucher
authors: Vera
authors: V
authors: Moskaleva
authors: Vladimir
authors: V
authors: Popenko
authors: Alexey
authors: A
authors: Shpak
authors: Vitaly
authors: V
authors: Shvets
authors: Leonid
authors: L
authors: Kozlov
authors: Alexander
authors: A
authors: Kaplun
mesh_terms: D000818:Animals; D015922:Complement C1q / Q000037:antagonists & inhibitors*; D003171:Complement Pathway, Classical / Q000187:drug effects*; D006168:Guinea Pigs; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008968:Molecular Conformation; D012756:Sheep; D013256:Steroids / Q000494:pharmacology*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D015922:Complement C1q; D007136:Immunoglobulins; D007202:Indicators and Reagents; D013256:Steroids; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid