title: Targeting human secretory phospholipase A2 with designed peptide inhibitors for inflammatory therapy.
abstract: Phospholipase A2 (PLA2) is potentially an important target for anti-inflammatory therapeutics. Here, we described a systematic scheme that integrated protein docking and peptide redocking, molecular dynamics simulation, and binding affinity analysis to rationally design PLA2 inhibitory peptides based on a solved PLA2 crystal structure. The scheme employed protein docking to sample the interaction modes of PLA2 with its natural inhibitor Clara cell protein, from which a number of peptide fragments, including a pentapeptide LLLGS, were cut off and redocked to serve as the lead entities of PLA2 inhibitory peptides. In addition, a systematic mutation energy map that characterized the binding free energy changes ΔG upon mutations of each position of the putative pentapeptide to 20 amino acids was also profiled, which was subsequently used to guide peptide structure optimization. In order to solidify the computational findings, we performed kinetic and inhibition studies of few designed peptides against human secretory PLA2. Consequently, eight peptides were successfully identified to have potent inhibition potency, in which the LLAYK and AVFRS were found to suppress enzymatic activity significantly (Ki = 0.75 ± 0.06 and 4.2 ± 0.3 μM, respectively). A further structure examination revealed that the designed peptides can form intensive nonpolar networks of van der Waals contacts and hydrophobic interactions at their complex interfaces with PLA2, conferring considerable stability and affinity for the formed complex systems.
authors.affiliation: Emergency Medical Center (Trauma Center), People's Hospital affiliated to Jiangsu University, Zhenjiang, China and.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Li
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Shao
authors.forename: Wenqin
authors.initials: W
authors.lastname: Zhou
authors.forename: Kuifeng
authors.initials: K
authors.lastname: Wang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D014598:Uteroglobin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D064801:Phospholipase A2 Inhibitors; D014598:Uteroglobin; D054497:Phospholipases A2, Secretory
keywords: Inflammation; peptide inhibitor; phospholipase A2; rational drug targeting