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- Title
Structure-Based Grafting, Mutation, and Optimization of Peptide Inhibitors to Fit in the Active Pocket of Human Secreted Phospholipase A2: Find New Use of Old Peptide Agents with Anti-Inflammatory Activity.
- Authors
Zhan, Chengye; Li, Shusheng; Zhong, Qiang; Zhou, Daixing
- Abstract
Phospholipase A2 ( PLA2) is a key enzyme in the production of diverse mediators of inflammatory conditions, which possesses an open active pocket that is physicochemically compatible with a variety of small-molecule substrates and peptide inhibitors. Although various peptides and peptide analogues have been identified to have inhibitory activity against PLA2 originated from animals and plants, only very few were designed for human secreted PLA2 (hs PLA2), an attractive target of inflammatory arthritis. Considering that the catalytic domains of PLA2 family members across different species are highly conserved in primary sequence, advanced structure, and biological function, in this study, we proposed a synthetic pipeline to implement structure-based grafting, mutation, and optimization of peptide ligands from the snake PLA2-peptide complex crystal structures into the active pocket of apo hs PLA2 structure to computationally generate a large number of potential peptide inhibitors for hs PLA2, and the hs PLA2 inhibitory potency of few highly promising candidates arising from the theoretical analysis was determined. As might be expected, three peptides FLSFK, FLVYK, and FISYR showed relatively high inhibitory capability against hs PLA2, and other three ALSYK, LVFYA, and KGAILGFM were also modestly potent as they can suppress the enzymatic activity with observable doses. Further, the designed peptide FLVYK with highest potency was carried out with structure-guided modification based on its atomic interactions with hs PLA2 using the computationally modeled structure data, consequently resulting in a dual-point mutant EL IYK with significantly increased activity.
- Subjects
INFLAMMATION treatment; ENZYME inhibitors; PHOSPHOLIPASE A2; IMMUNOLOGY of inflammation; ANTI-inflammatory agents; CHEMICAL synthesis; SURFACE grafting (Polymer chemistry); PEPTIDE synthesis; GENETIC mutation
- Publication
Chemical Biology & Drug Design, 2015, Vol 85, Issue 4, p418
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12424