Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death
Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death(89 views) Russo L, Mascanzoni F, Farina B, Dolga AM, Monti A, Caporale A, Culmsee C, Fattorusso R, Ruvo M, Doti N
J Med Chem (ISSN: 0022-2623linking, 0022-2623print), 2021 Aug 12; 64
(15
): 11445-11459.
Keywords: Animals
, Apoptosis Drug Effects
, Apoptosis Inducing Factor Chemical Synthesis Chemistry Pharmacology
, Brain Injuries Drug Therapy
, Cell Death Drug Effects
, Cell Survival Drug Effects
, Cultured
, Cyclophilin A Antagonists, Inhibitors Metabolism
, Dose-Response Relationship, Drug Design
, Glutamic Acid Metabolism
, Humans
, Molecular Structure
, Structure-Activity Relationship,
Affiliations: *** IBB - CNR ***
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy.
Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy.
Institute of Pharmacology and Clinical Pharmacy, University of Marburg, 35043 Marburg, Germany.
Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), Research School of Behavioural and Cognitive Neurosciences (BCN), Department of Molecular Pharmacology, University of Groningen, 9713 AV Groningen, The Netherlands.
References: Not available.
Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death
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.
Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death
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Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death