Abstract—Petrosaspongiolides M–R (PM–PR, 1–5) are marine sesterterpenes structurally characterised by a g-hydroxybutenolide moiety. They have shown an in vitro and in vivo potent anti-inflammatory activity, mediated by specific inhibition of secretory phospholipase A2 (sPLA2 enzymes). The molecular mechanism underlying the sub-micromolar irreversible inhibition of the beevenom PLA2 (bvPLA2) by PM has been clarified combining mass spectrometry (MS) and molecular modelling approaches. The Nterminal amino group (Ile-1 residue), recently identified as the unique PM covalent binding site on this enzyme, selectively delivers a nucleophilic attack onto the masked aldehyde at C-25 of the pharmacophoric g-hydroxybutenolide ring of PM, giving rise to a Schiff base. In the attempt of broadening the knowledge of the mechanism at molecular level of PLA2 inactivation by this family of compounds, we performed a comparative analysis on petrosaspongiolides M-R, whose results are discussed in this paper. Firstly, the amount of bvPLA2 enzyme covalently modified after incubation with each of petrosaspongiolides M-R was measured and resulted to be in good agreement with pharmacological in vitro data. Then, a full characterisation of the bvPLA2 adduct with PR, one of the least active and most structurally different among petrosaspongiolides, by LC-MS, MSn, and computational methods, confirmed the same inhibition mechanism and covalent binding site already found for PM. Finally, extensive molecular docking studies performed in comparison on the PM–PLA2 and PR–PLA2 complexes provided critical insight on how the balance between non-covalent and covalent inhibitor-enzyme interactions may affect the final potency exhibited by the various compounds of the petrosaspongiolide family.

Further Insights on the Structural Aspects of PLA2 Inhibition by g-hydroxybutenolide-containing Natural Products: a Comparative Study on Petrosaspongiolides M-R / Monti, Maria Chiara; Casapullo, Agostino; Riccio, Raffaele; GOMEZ PALOMA, L.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 12:(2004), pp. 1467-1474. [10.1016/j.bmc.2003.12.038]

Further Insights on the Structural Aspects of PLA2 Inhibition by g-hydroxybutenolide-containing Natural Products: a Comparative Study on Petrosaspongiolides M-R

MONTI, Maria Chiara;CASAPULLO, Agostino;RICCIO, Raffaele;
2004

Abstract

Abstract—Petrosaspongiolides M–R (PM–PR, 1–5) are marine sesterterpenes structurally characterised by a g-hydroxybutenolide moiety. They have shown an in vitro and in vivo potent anti-inflammatory activity, mediated by specific inhibition of secretory phospholipase A2 (sPLA2 enzymes). The molecular mechanism underlying the sub-micromolar irreversible inhibition of the beevenom PLA2 (bvPLA2) by PM has been clarified combining mass spectrometry (MS) and molecular modelling approaches. The Nterminal amino group (Ile-1 residue), recently identified as the unique PM covalent binding site on this enzyme, selectively delivers a nucleophilic attack onto the masked aldehyde at C-25 of the pharmacophoric g-hydroxybutenolide ring of PM, giving rise to a Schiff base. In the attempt of broadening the knowledge of the mechanism at molecular level of PLA2 inactivation by this family of compounds, we performed a comparative analysis on petrosaspongiolides M-R, whose results are discussed in this paper. Firstly, the amount of bvPLA2 enzyme covalently modified after incubation with each of petrosaspongiolides M-R was measured and resulted to be in good agreement with pharmacological in vitro data. Then, a full characterisation of the bvPLA2 adduct with PR, one of the least active and most structurally different among petrosaspongiolides, by LC-MS, MSn, and computational methods, confirmed the same inhibition mechanism and covalent binding site already found for PM. Finally, extensive molecular docking studies performed in comparison on the PM–PLA2 and PR–PLA2 complexes provided critical insight on how the balance between non-covalent and covalent inhibitor-enzyme interactions may affect the final potency exhibited by the various compounds of the petrosaspongiolide family.
2004
Further Insights on the Structural Aspects of PLA2 Inhibition by g-hydroxybutenolide-containing Natural Products: a Comparative Study on Petrosaspongiolides M-R / Monti, Maria Chiara; Casapullo, Agostino; Riccio, Raffaele; GOMEZ PALOMA, L.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 12:(2004), pp. 1467-1474. [10.1016/j.bmc.2003.12.038]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/951348
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