Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease
The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Biochemistry and Biophysics Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580821000376 |
| _version_ | 1818837212922380288 |
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| author | Izzeddin Alsalahat Zubida M. Al-Majdoub Mutasem O. Taha Jill Barber Harmesh Aojula Nigel Hodson Sally Freeman |
| author_facet | Izzeddin Alsalahat Zubida M. Al-Majdoub Mutasem O. Taha Jill Barber Harmesh Aojula Nigel Hodson Sally Freeman |
| author_sort | Izzeddin Alsalahat |
| collection | DOAJ |
| description | The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent bonding between specific functional groups (nucleophiles) within the Aβ peptide and the beta-lactam ring. Mass spectrometry and computational docking supported covalent modification of Aβ by BP. BP was found to inhibit aggregation of Aβ as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aβ-induced cell cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. The specific interaction of BP with Aβ suggests the possibility of structure-based drug design, leading to the identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders such as AD. |
| first_indexed | 2024-12-19T03:18:55Z |
| format | Article |
| id | doaj.art-2b65d79699e9452e8c0e4c4c4b236517 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-19T03:18:55Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-2b65d79699e9452e8c0e4c4c4b2365172022-12-21T20:37:49ZengElsevierBiochemistry and Biophysics Reports2405-58082021-07-0126100943Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's diseaseIzzeddin Alsalahat0Zubida M. Al-Majdoub1Mutasem O. Taha2Jill Barber3Harmesh Aojula4Nigel Hodson5Sally Freeman6Division of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman, 11931, Jordan; Corresponding author. Division of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UKDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, JordanCentre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UKDivision of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UKBioAFM Facility, Faculty of Biology, Medicine and Health, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UKDivision of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; Corresponding author.The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent bonding between specific functional groups (nucleophiles) within the Aβ peptide and the beta-lactam ring. Mass spectrometry and computational docking supported covalent modification of Aβ by BP. BP was found to inhibit aggregation of Aβ as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aβ-induced cell cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. The specific interaction of BP with Aβ suggests the possibility of structure-based drug design, leading to the identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders such as AD.http://www.sciencedirect.com/science/article/pii/S2405580821000376Alzheimer's diseaseAmyloid-betaBenzylpenicillinThioflavin TAtomic force microscopyMass spectrometry |
| spellingShingle | Izzeddin Alsalahat Zubida M. Al-Majdoub Mutasem O. Taha Jill Barber Harmesh Aojula Nigel Hodson Sally Freeman Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease Biochemistry and Biophysics Reports Alzheimer's disease Amyloid-beta Benzylpenicillin Thioflavin T Atomic force microscopy Mass spectrometry |
| title | Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease |
| title_full | Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease |
| title_fullStr | Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease |
| title_full_unstemmed | Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease |
| title_short | Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease |
| title_sort | inhibition of aggregation of amyloid β through covalent modification with benzylpenicillin potential relevance to alzheimer s disease |
| topic | Alzheimer's disease Amyloid-beta Benzylpenicillin Thioflavin T Atomic force microscopy Mass spectrometry |
| url | http://www.sciencedirect.com/science/article/pii/S2405580821000376 |
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