Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition

© 2020 Piyapan Suwanttananuruk et al., published by De Gruyter 2020. Amyloid cascade, one of pathogenic pathways of Alzheimer's disease (AD), was focused as one of drug discovery targets. In this study, β-secretase (BACE1) inhibitors were designed aiming at the development of multifunctional co...

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Main Authors: Piyapan Suwanttananuruk, Jutamas Jiaranaikulwanitch, Pornthip Waiwut, Opa Vajragupta
Format: Journal
Published: 2020
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/70409
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Institution: Chiang Mai University
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spelling th-cmuir.6653943832-704092020-10-14T08:39:13Z Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition Piyapan Suwanttananuruk Jutamas Jiaranaikulwanitch Pornthip Waiwut Opa Vajragupta Chemistry Materials Science © 2020 Piyapan Suwanttananuruk et al., published by De Gruyter 2020. Amyloid cascade, one of pathogenic pathways of Alzheimer's disease (AD), was focused as one of drug discovery targets. In this study, β-secretase (BACE1) inhibitors were designed aiming at the development of multifunctional compounds targeting amyloid pathogenic cascade. Tryptophan was used as a core structure due to its properties of the central nervous system (CNS) penetration and BACE1 inhibition activity. Three amino acid residues and guanidine were selected as linkers to connect the tryptophan core structure and the extended aromatic moieties. The distance between the aromatic systems of the core structure and the extended moieties was kept at the optimal length for amyloid-β (Aβ) peptide binding to inhibit its fibrillation and aggregation. Sixteen designed compounds were evaluated in silico. Eight hit compounds of TSR and TGN series containing serine and guanidine linkers, respectively, were identified and synthesized based on docking results. TSR2 and TGN2 were found to exert strong actions as BACE1 (IC50 24.18 μM and 22.35 μM) and amyloid aggregation inhibitors (IC50 37.06 μM and 36.12 μM). Only TGN2 demonstrated a neuroprotective effect in SH-SY5Y cells by significantly reducing Aβ-induced cell death at a concentration of 2.62 μM. These results support the validity of multifunctional approaches to inhibition of the β-amyloid cascade. 2020-10-14T08:29:50Z 2020-10-14T08:29:50Z 2020-01-01 Journal 23915420 2-s2.0-85086908160 10.1515/chem-2020-0067 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85086908160&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/70409
institution Chiang Mai University
building Chiang Mai University Library
continent Asia
country Thailand
Thailand
content_provider Chiang Mai University Library
collection CMU Intellectual Repository
topic Chemistry
Materials Science
spellingShingle Chemistry
Materials Science
Piyapan Suwanttananuruk
Jutamas Jiaranaikulwanitch
Pornthip Waiwut
Opa Vajragupta
Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
description © 2020 Piyapan Suwanttananuruk et al., published by De Gruyter 2020. Amyloid cascade, one of pathogenic pathways of Alzheimer's disease (AD), was focused as one of drug discovery targets. In this study, β-secretase (BACE1) inhibitors were designed aiming at the development of multifunctional compounds targeting amyloid pathogenic cascade. Tryptophan was used as a core structure due to its properties of the central nervous system (CNS) penetration and BACE1 inhibition activity. Three amino acid residues and guanidine were selected as linkers to connect the tryptophan core structure and the extended aromatic moieties. The distance between the aromatic systems of the core structure and the extended moieties was kept at the optimal length for amyloid-β (Aβ) peptide binding to inhibit its fibrillation and aggregation. Sixteen designed compounds were evaluated in silico. Eight hit compounds of TSR and TGN series containing serine and guanidine linkers, respectively, were identified and synthesized based on docking results. TSR2 and TGN2 were found to exert strong actions as BACE1 (IC50 24.18 μM and 22.35 μM) and amyloid aggregation inhibitors (IC50 37.06 μM and 36.12 μM). Only TGN2 demonstrated a neuroprotective effect in SH-SY5Y cells by significantly reducing Aβ-induced cell death at a concentration of 2.62 μM. These results support the validity of multifunctional approaches to inhibition of the β-amyloid cascade.
format Journal
author Piyapan Suwanttananuruk
Jutamas Jiaranaikulwanitch
Pornthip Waiwut
Opa Vajragupta
author_facet Piyapan Suwanttananuruk
Jutamas Jiaranaikulwanitch
Pornthip Waiwut
Opa Vajragupta
author_sort Piyapan Suwanttananuruk
title Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
title_short Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
title_full Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
title_fullStr Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
title_full_unstemmed Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
title_sort lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
publishDate 2020
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85086908160&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/70409
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