Cargando…
5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation
[Image: see text] Protein misfolding results in a plethora of known diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic sm...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249125/ https://www.ncbi.nlm.nih.gov/pubmed/37305264 http://dx.doi.org/10.1021/acsomega.3c02668 |
_version_ | 1785055494746931200 |
---|---|
author | Ramirez, Eduardo Ganegamage, Susantha K. Elbatrawy, Ahmed A. Alnakhala, Heba Shimanaka, Kazuma Tripathi, Arati Min, Sehong Rochet, Jean-Christophe Dettmer, Ulf Fortin, Jessica S. |
author_facet | Ramirez, Eduardo Ganegamage, Susantha K. Elbatrawy, Ahmed A. Alnakhala, Heba Shimanaka, Kazuma Tripathi, Arati Min, Sehong Rochet, Jean-Christophe Dettmer, Ulf Fortin, Jessica S. |
author_sort | Ramirez, Eduardo |
collection | PubMed |
description | [Image: see text] Protein misfolding results in a plethora of known diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic small molecules with the ability to reduce protein misfolding, we evaluated a set of 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) and its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), and triazine (5) linker. In addition, we explored small modifications on a very potent antioligomer 5-nitro-1,2-benzothiazol-3-amine (5-NBA) (compounds 6–13). This study aims to define the activity of BTA and its derivatives on a variety of prone-to-aggregate proteins such as transthyretin (TTR(81–127), TTR(101–125)), α-synuclein (α-syn), and tau isoform 2N4R (tau 2N4R) through various biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation of the previously mentioned proteins after treatment with BTA and its derivatives. Antifibrillary activity was confirmed using transmission electron microscopy (TEM). Photoreactive cross-linking assay (PICUP) was utilized to detect antioligomer activity and lead to the identification of 5-NBA (at low micromolar concentration) and compound 13 (at high concentration) as the most promising in reducing oligomerization. 5-NBA and not BTA inhibited the inclusion formation based on the cell-based assay using M17D neuroblastoma cells that express inclusion-prone αS-3K::YFP. 5-NBA abrogated the fibril, oligomer, and inclusion formation in a dose-dependent manner. 5-NBA derivatives could be the key to mitigate protein aggregation. In the future, the results made from this study will provide an initial platform to generate more potent inhibitors of α-syn and tau 2N4R oligomer and fibril formation. |
format | Online Article Text |
id | pubmed-10249125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-102491252023-06-09 5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation Ramirez, Eduardo Ganegamage, Susantha K. Elbatrawy, Ahmed A. Alnakhala, Heba Shimanaka, Kazuma Tripathi, Arati Min, Sehong Rochet, Jean-Christophe Dettmer, Ulf Fortin, Jessica S. ACS Omega [Image: see text] Protein misfolding results in a plethora of known diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic small molecules with the ability to reduce protein misfolding, we evaluated a set of 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) and its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), and triazine (5) linker. In addition, we explored small modifications on a very potent antioligomer 5-nitro-1,2-benzothiazol-3-amine (5-NBA) (compounds 6–13). This study aims to define the activity of BTA and its derivatives on a variety of prone-to-aggregate proteins such as transthyretin (TTR(81–127), TTR(101–125)), α-synuclein (α-syn), and tau isoform 2N4R (tau 2N4R) through various biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation of the previously mentioned proteins after treatment with BTA and its derivatives. Antifibrillary activity was confirmed using transmission electron microscopy (TEM). Photoreactive cross-linking assay (PICUP) was utilized to detect antioligomer activity and lead to the identification of 5-NBA (at low micromolar concentration) and compound 13 (at high concentration) as the most promising in reducing oligomerization. 5-NBA and not BTA inhibited the inclusion formation based on the cell-based assay using M17D neuroblastoma cells that express inclusion-prone αS-3K::YFP. 5-NBA abrogated the fibril, oligomer, and inclusion formation in a dose-dependent manner. 5-NBA derivatives could be the key to mitigate protein aggregation. In the future, the results made from this study will provide an initial platform to generate more potent inhibitors of α-syn and tau 2N4R oligomer and fibril formation. American Chemical Society 2023-05-23 /pmc/articles/PMC10249125/ /pubmed/37305264 http://dx.doi.org/10.1021/acsomega.3c02668 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Ramirez, Eduardo Ganegamage, Susantha K. Elbatrawy, Ahmed A. Alnakhala, Heba Shimanaka, Kazuma Tripathi, Arati Min, Sehong Rochet, Jean-Christophe Dettmer, Ulf Fortin, Jessica S. 5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation |
title | 5-Nitro-1,2-benzothiazol-3-amine
and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
Modulate α-Synuclein and Tau Aggregation |
title_full | 5-Nitro-1,2-benzothiazol-3-amine
and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
Modulate α-Synuclein and Tau Aggregation |
title_fullStr | 5-Nitro-1,2-benzothiazol-3-amine
and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
Modulate α-Synuclein and Tau Aggregation |
title_full_unstemmed | 5-Nitro-1,2-benzothiazol-3-amine
and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
Modulate α-Synuclein and Tau Aggregation |
title_short | 5-Nitro-1,2-benzothiazol-3-amine
and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
Modulate α-Synuclein and Tau Aggregation |
title_sort | 5-nitro-1,2-benzothiazol-3-amine
and n-ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide
modulate α-synuclein and tau aggregation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249125/ https://www.ncbi.nlm.nih.gov/pubmed/37305264 http://dx.doi.org/10.1021/acsomega.3c02668 |
work_keys_str_mv | AT ramirezeduardo 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT ganegamagesusanthak 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT elbatrawyahmeda 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT alnakhalaheba 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT shimanakakazuma 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT tripathiarati 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT minsehong 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT rochetjeanchristophe 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT dettmerulf 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation AT fortinjessicas 5nitro12benzothiazol3amineandnethyl1ethylcarbamoyl5nitro12benzothiazol3ylaminoformamidemodulateasynucleinandtauaggregation |