A cationic amphiphilic peptide chaperone rescues Aβ 42 aggregation and cytotoxicity.

Autor: Puneeth Kumar DR; Department of Chemistry, Indian Institute of Science Education and Research Dr. Homi Bhabha Road, Pashan Pune-411008 India hn.gopi@iiserpune.ac.in., Reja RM; Department of Chemistry, Indian Institute of Science Education and Research Dr. Homi Bhabha Road, Pashan Pune-411008 India hn.gopi@iiserpune.ac.in., Senapati DK; NMR Research Centre, Indian Institute of Science Bangalore-560012 India., Singh M; Department of Chemistry, Indian Institute of Science Education and Research Dr. Homi Bhabha Road, Pashan Pune-411008 India hn.gopi@iiserpune.ac.in., Nalawade SA; Department of Chemistry, Indian Institute of Science Education and Research Dr. Homi Bhabha Road, Pashan Pune-411008 India hn.gopi@iiserpune.ac.in., George G; NMR Research Centre, Indian Institute of Science Bangalore-560012 India., Kaul G; Division of Microbiology and Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute Sitapur Road, Sector 10, Janakipuram Extension Lucknow-226031 Uttar Pradesh India.; AcSIR: Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India., Akhir A; Division of Microbiology and Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute Sitapur Road, Sector 10, Janakipuram Extension Lucknow-226031 Uttar Pradesh India., Chopra S; Division of Microbiology and Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute Sitapur Road, Sector 10, Janakipuram Extension Lucknow-226031 Uttar Pradesh India.; AcSIR: Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India., Raghothama S; NMR Research Centre, Indian Institute of Science Bangalore-560012 India., Gopi HN; Department of Chemistry, Indian Institute of Science Education and Research Dr. Homi Bhabha Road, Pashan Pune-411008 India hn.gopi@iiserpune.ac.in.
Jazyk: angličtina
Zdroj: RSC medicinal chemistry [RSC Med Chem] 2022 Dec 10; Vol. 14 (2), pp. 332-340. Date of Electronic Publication: 2022 Dec 10 (Print Publication: 2023).
DOI: 10.1039/d2md00414c
Abstrakt: Directing Aβ 42 to adopt a conformation that is free from aggregation and cell toxicity is an attractive and viable strategy to design therapeutics for Alzheimer's disease. Over the years, extensive efforts have been made to disrupt the aggregation of Aβ 42 using various types of inhibitors but with limited success. Herein, we report the inhibition of aggregation of Aβ 42 and disintegration of matured fibrils of Aβ 42 into smaller assemblies by a 15-mer cationic amphiphilic peptide. The biophysical analysis comprising thioflavin T (ThT) mediated amyloid aggregation kinetic analysis, dynamic light scattering, ELISA, AFM, and TEM suggested that the peptide effectively disrupts Aβ 42 aggregation. The circular dichroism (CD) and 2D-NMR HSQC analysis reveal that upon interaction, the peptide induces a conformational change in Aβ 42 that is free from aggregation. Further, the cell assay experiments revealed that this peptide is non-toxic to cells and also rescues the cells from the toxicity of Aβ 42 . Peptides with a shorter length displayed either weak or no inhibitory effect on Aβ 42 aggregation and cytotoxicity. These results suggest that the 15-residue cationic amphiphilic peptide reported here may serve as a potential therapeutic candidate for Alzheimer's disease.
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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