Fabrizio Dal Piaz1, Piera Ferro2, Antonio Vassallo3, Michele Vasaturo2, Giovanni Forte2, Maria Giovanna Chini2, Giuseppe Bifulco2, Alessandra Tosco4, Nunziatina De Tommasi2. 1. Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy. Electronic address: fdalpiaz@unisa.it. 2. Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy. 3. Department of Sciences, University of Basilicata, Via Nazario Sauro 85, 85100 Potenza, SA, Italy. 4. Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy. Electronic address: tosco@unisa.it.
Abstract
BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP-1) activity has been implicated in the pathogenesis of numerous diseases as cancer, inflammation, diabetes and neurodegenerative disorders, therefore the research for new PARP-1 inhibitors is still an active area. METHODS: To identify new potential PARP-1 inhibitors, we performed a screening of a small-molecule library consisting of polyphenols isolated from plants used in the traditional medicine, by Surface Plasmon Resonance (SPR). Biochemical and cellular assays were performed to confirm SPR results and select the promising candidate(s). Finally, limited proteolysis and ligand docking analyses allowed defining the protein region involved in the interaction with the putative inhibitor(s). RESULTS: The dimeric spiro-flavonoid 2″-hydroxygenkwanol A, member of a relatively recently discovered class of flavonoids containing a spirane C-atom, has been identified as possible PARP-1 inhibitor. This compound showed a high affinity for the polymerase (KD: 0.32±0.05μM); moreover PARP-1 activity in the presence of 2″-hydroxygenkwanol A was significantly affected both when using the recombinant protein and when measuring the cellular effects. Finally, our study suggests this compound to efficiently interact with the protein catalytic domain, into the nicotine binding pocket. CONCLUSION: 2″-hydroxygenkwanol A efficiently binds and inhibits PARP-1 at submicromolar concentrations, thus representing a promising lead for the design of a new class of PARP-1 modulators, useful as therapeutic agents and/or biochemical tools. GENERAL SIGNIFICANCE: Our study has identified an additional class of plant molecules, the spiro-biflavonoids, with known beneficial pharmacological properties but with an unknown mechanism of action, as a possible novel class of PARP-1 activity inhibitors.
BACKGROUND:Poly(ADP-ribose) polymerase 1 (PARP-1) activity has been implicated in the pathogenesis of numerous diseases as cancer, inflammation, diabetes and neurodegenerative disorders, therefore the research for new PARP-1 inhibitors is still an active area. METHODS: To identify new potential PARP-1 inhibitors, we performed a screening of a small-molecule library consisting of polyphenols isolated from plants used in the traditional medicine, by Surface Plasmon Resonance (SPR). Biochemical and cellular assays were performed to confirm SPR results and select the promising candidate(s). Finally, limited proteolysis and ligand docking analyses allowed defining the protein region involved in the interaction with the putative inhibitor(s). RESULTS: The dimeric spiro-flavonoid 2″-hydroxygenkwanol A, member of a relatively recently discovered class of flavonoids containing a spirane C-atom, has been identified as possible PARP-1 inhibitor. This compound showed a high affinity for the polymerase (KD: 0.32±0.05μM); moreover PARP-1 activity in the presence of 2″-hydroxygenkwanol A was significantly affected both when using the recombinant protein and when measuring the cellular effects. Finally, our study suggests this compound to efficiently interact with the protein catalytic domain, into the nicotine binding pocket. CONCLUSION: 2″-hydroxygenkwanol A efficiently binds and inhibits PARP-1 at submicromolar concentrations, thus representing a promising lead for the design of a new class of PARP-1 modulators, useful as therapeutic agents and/or biochemical tools. GENERAL SIGNIFICANCE: Our study has identified an additional class of plant molecules, the spiro-biflavonoids, with known beneficial pharmacological properties but with an unknown mechanism of action, as a possible novel class of PARP-1 activity inhibitors.
Authors: Stefania Terracciano; Alessandra Russo; Maria G Chini; Maria C Vaccaro; Marianna Potenza; Antonio Vassallo; Raffaele Riccio; Giuseppe Bifulco; Ines Bruno Journal: Sci Rep Date: 2018-01-26 Impact factor: 4.379
Authors: Ashraf N Abdalla; Mohamed E Abdallah; Akhmed Aslam; Ammar Bader; Antonio Vassallo; Nunziatina De Tommasi; Waleed H Malki; Ahmed M Gouda; Mohammed H Mukhtar; Mahmoud Zaki El-Readi; Hamad M Alkahtani; Alaa A-M Abdel-Aziz; Adel S El-Azab Journal: Molecules Date: 2020-05-08 Impact factor: 4.411