1. Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death.
- Author
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Russo L, Mascanzoni F, Farina B, Dolga AM, Monti A, Caporale A, Culmsee C, Fattorusso R, Ruvo M, and Doti N
- Subjects
- Animals, Apoptosis Inducing Factor chemical synthesis, Apoptosis Inducing Factor chemistry, Cell Survival drug effects, Cells, Cultured, Cyclophilin A metabolism, Dose-Response Relationship, Drug, Glutamic Acid metabolism, Humans, Mice, Molecular Structure, Structure-Activity Relationship, Apoptosis drug effects, Apoptosis Inducing Factor pharmacology, Brain Injuries drug therapy, Cell Death drug effects, Cyclophilin A antagonists & inhibitors, Drug Design
- Abstract
Blocking the interaction between the apoptosis-inducing factor (AIF) and cyclophilin A (CypA) by the AIF fragment AIF(370-394) is protective against glutamate-induced neuronal cell death and brain injury in mice. Starting from AIF(370-394), we report the generation of the disulfide-bridged and shorter variant AIF(381-389) and its structural characterization by nuclear magnetic resonance (NMR) in the free and CypA-bound state. AIF(381-389) in both the free and bound states assumes a β-hairpin conformation similar to that of the fragment in the AIF protein and shows a highly reduced conformational flexibility. This peptide displays a similar in vitro affinity for CypA, an improved antiapoptotic activity in cells and an enhanced proteolytic stability compared to the parent peptide. The NMR-based 3D model of the AIF(381-389)/CypA complex provides a better understanding of the binding hot spots on both the peptide and the protein and can be exploited to design AIF/CypA inhibitors with improved pharmacokinetic and pharmacodynamics features. more...
- Published
- 2021
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