Molecular Basis of Phospholipase A2 Inhibition by Petrosaspongiolide M

PLA2‐mediated catalytic activation of its inhibitor 25‐acetyl‐petrosaspongiolide M: serendipitous identification of a new PLA2suicide inhibitor

“…It should be noted that the protein species with two oxy-Met residues is not affected by PM. M86, the second oxy-Met, lies in the proximity of the active site, protruding its side chain towards the pocket where PM binding takes place; we consider therefore likely that the extra oxygen atom may interfere with optimal positioning of PM for covalent binding (see also [9]) lyzed hydrolysis of the C-25 acetate would generate the reactive PM with the consequent covalent inhibition of the enzyme, as already shown in our previous work [9]. This suicide mechanism postulated on the basis of these considerations (Scheme 1) gives evidence of the formation of an imine intermediate, as confirmed by the mass increment of 444 Da observed for the modified PLA 2 species (after reduction) [9,10].…”

“…Among them, petrosaspongiolides M-R, isolated in 1997 from the marine sponge Petrosaspongia nigra [8], have recently become the subject of extensive investigation in our laboratory, in the attempt to clarify their mechanism of inhibition and their interaction at the atomic level with bvPLA 2 . The ultimate goal of our study is a deep comprehension of the principles underlying the mode of action of this family of anti-inflammatory natural agents [9,10]. In fact, armed with such knowledge, we aim at a rational design of simplified inhibitors of PLA 2 as potential new leads for the treatment of inflammation-related diseases [11][12][13][14][15][16][17][18][19].…”

“…Petrosaspongiolide M (PM) (2), the most active among petrosaspongiolides [8,20,21], is able to covalently and specifically modify bvPLA 2 by means of a Schiff base formation between its C-25 masked aldehyde moiety (a cyclic hemiacetal function) and the amino group of the N-terminal Ile-1 residue of the enzyme [9]. 3D models of the complexes between bvPLA 2 and petrosaspongiolides M and R, respectively, were obtained by means of molecular modeling studies, leading us to a better understanding of the enzyme inactivation process at a molecular level.…”

PDE4 inhibitors: From Discovery and Announced Failure to its Resurgence

“…68 Uma segunda hipótese considera que estes efeitos secundários são causados pela interação com o sítio de alta afinidade, chamado de sítio de ligação de alta afinidade do rolipram (11), no sistema nervoso central e em células secretoras de ácido gástrico. 69 Outra proposição enfatiza que a inibição de uma isoforma específica de PDE4, mais provavelmente a PDE4D, seria a fonte dos efeitos eméticos ocorridos com a utilização de inibidores desta família enzimática. 68, [70][71][72] No entanto, ainda não se tem uma resposta definitiva de qual dos mecanismos descritos, ou até mesmo um novo, seria o real responsável pelos efeitos colaterais.…”

Marine natural products targeting phospholipases A2

“…The sesterterpene manoalide (20), which was isolated for the first time in the early 1980s from the sponge Luffariella variabilis by Scheuer et al [26], became the first marine natural product reported as PLA 2 inhibitor, and it remains, to date, the most investigated marine PLA 2 antagonist. The PLA 2 inhibiting properties of manoalide (20) were discovered simultaneously by research groups lead by Edward Dennis [4] and by Robert Jacobs Noteworthy, the nudibranch derived compounds, which include luffariellins C (26) and D (27), and deoxymanoalide 28 activity is a ten-fold weaker than the ones observed in the sponges [29,30] Petrosaspongiolide M (34) also inhibits the expression of iNOS and COX-2, and, as a result, the production of NO and PGE 2 , respectively, and NF-B activation [30,[32][33][34][35]. Studies performed by Monti et al have revealed that, although scalaradial (35) does bind covalently to bee venom PLA 2 , the key step in the PLA 2 inhibitory activity of scalaradial (35) is, as observed with petrosaspongiolide M (34), its nonvalent binding to the enzyme's active site [33].…”