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3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3

Dahlqvist, Alexander LU ; Mandal, Santanu LU ; Peterson, Kristoffer LU ; Håkansson, Maria LU ; Logan, Derek T. LU ; Zetterberg, Fredrik R. ; Leffler, Hakon LU and Nilsson, Ulf J. LU (2019) In Molecules 24(24).
Abstract

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... (More)

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.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
C-galactosyl, Galectin-3, Inhibitor, Naphthamide, Selectivity
in
Molecules
volume
24
issue
24
article number
4554
publisher
Molecular Diversity Preservation International
external identifiers
  • scopus:85076704383
  • pmid:31842451
ISSN
1420-3049
DOI
10.3390/molecules24244554
language
English
LU publication?
yes
id
1e03e24d-4176-455c-97c1-c8b623d929ab
date added to LUP
2020-01-03 13:31:42
date last changed
2020-01-08 08:58:29
@article{1e03e24d-4176-455c-97c1-c8b623d929ab,
  abstract     = {<p>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.</p>},
  author       = {Dahlqvist, Alexander and Mandal, Santanu and Peterson, Kristoffer and Håkansson, Maria and Logan, Derek T. and Zetterberg, Fredrik R. and Leffler, Hakon and Nilsson, Ulf J.},
  issn         = {1420-3049},
  language     = {eng},
  month        = {12},
  number       = {24},
  publisher    = {Molecular Diversity Preservation International},
  series       = {Molecules},
  title        = {3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3},
  url          = {http://dx.doi.org/10.3390/molecules24244554},
  doi          = {10.3390/molecules24244554},
  volume       = {24},
  year         = {2019},
}