Cargando…
3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3
The galectins are a family of galactose-binding proteins playing key roles in inflammatory processes and cancer. However, they are structurally very closely related, and discovery of highly selective inhibitors is challenging. In this work, we report the design of novel inhibitors binding to a subsi...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943516/ https://www.ncbi.nlm.nih.gov/pubmed/31842451 http://dx.doi.org/10.3390/molecules24244554 |
_version_ | 1783484891269169152 |
---|---|
author | Dahlqvist, Alexander Mandal, Santanu Peterson, Kristoffer Håkansson, Maria Logan, Derek T. Zetterberg, Fredrik R. Leffler, Hakon Nilsson, Ulf J. |
author_facet | Dahlqvist, Alexander Mandal, Santanu Peterson, Kristoffer Håkansson, Maria Logan, Derek T. Zetterberg, Fredrik R. Leffler, Hakon Nilsson, Ulf J. |
author_sort | Dahlqvist, Alexander |
collection | PubMed |
description | The galectins are a family of galactose-binding proteins playing key roles in inflammatory processes and cancer. However, they are structurally very closely related, and discovery of highly selective inhibitors is challenging. In this work, we report the design of novel inhibitors binding to a subsite unique to galectin-3, which confers both high selectivity and affinity towards galectin-3. Olefin cross metathesis between allyl β-C-galactopyranosyl and 1-vinylnaphthalenes or acylation of aminomethyl β-C-galactopyranosyl with 1-naphthoic acid derivatives gave C-galactopyranosyls carrying 1-naphthamide structural elements that interacted favorably with a galectin-3 unique subsite according to molecular modeling and X-ray structural analysis of two inhibitor-galectin-3 complexes. Affinities were down to sub-µM and selectivities over galectin-1, 2, 4 N-terminal domain, 4 C-terminal domain, 7, 8 N-terminal domain, 9 N-terminal domain, and 9 C-terminal domain were high. These results show that high affinity and selectivity for a single galectin can be achieved by targeting unique subsites, which holds promise for further development of small and selective galectin inhibitors. |
format | Online Article Text |
id | pubmed-6943516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69435162020-01-10 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 Dahlqvist, Alexander Mandal, Santanu Peterson, Kristoffer Håkansson, Maria Logan, Derek T. Zetterberg, Fredrik R. Leffler, Hakon Nilsson, Ulf J. Molecules Article The galectins are a family of galactose-binding proteins playing key roles in inflammatory processes and cancer. However, they are structurally very closely related, and discovery of highly selective inhibitors is challenging. In this work, we report the design of novel inhibitors binding to a subsite unique to galectin-3, which confers both high selectivity and affinity towards galectin-3. Olefin cross metathesis between allyl β-C-galactopyranosyl and 1-vinylnaphthalenes or acylation of aminomethyl β-C-galactopyranosyl with 1-naphthoic acid derivatives gave C-galactopyranosyls carrying 1-naphthamide structural elements that interacted favorably with a galectin-3 unique subsite according to molecular modeling and X-ray structural analysis of two inhibitor-galectin-3 complexes. Affinities were down to sub-µM and selectivities over galectin-1, 2, 4 N-terminal domain, 4 C-terminal domain, 7, 8 N-terminal domain, 9 N-terminal domain, and 9 C-terminal domain were high. These results show that high affinity and selectivity for a single galectin can be achieved by targeting unique subsites, which holds promise for further development of small and selective galectin inhibitors. MDPI 2019-12-12 /pmc/articles/PMC6943516/ /pubmed/31842451 http://dx.doi.org/10.3390/molecules24244554 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dahlqvist, Alexander Mandal, Santanu Peterson, Kristoffer Håkansson, Maria Logan, Derek T. Zetterberg, Fredrik R. Leffler, Hakon Nilsson, Ulf J. 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title | 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title_full | 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title_fullStr | 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title_full_unstemmed | 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title_short | 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3 |
title_sort | 3-substituted 1-naphthamidomethyl-c-galactosyls interact with two unique sub-sites for high-affinity and high-selectivity inhibition of galectin-3 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943516/ https://www.ncbi.nlm.nih.gov/pubmed/31842451 http://dx.doi.org/10.3390/molecules24244554 |
work_keys_str_mv | AT dahlqvistalexander 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT mandalsantanu 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT petersonkristoffer 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT hakanssonmaria 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT loganderekt 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT zetterbergfredrikr 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT lefflerhakon 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 AT nilssonulfj 3substituted1naphthamidomethylcgalactosylsinteractwithtwouniquesubsitesforhighaffinityandhighselectivityinhibitionofgalectin3 |