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...

Descripción completa

Detalles Bibliográficos
Autores principales: Dahlqvist, Alexander, Mandal, Santanu, Peterson, Kristoffer, Håkansson, Maria, Logan, Derek T., Zetterberg, Fredrik R., Leffler, Hakon, Nilsson, Ulf J.
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