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.
(Less)
- author
- 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
- organization
- publishing date
- 2019-12-12
- 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
- MDPI AG
- external identifiers
-
- pmid:31842451
- scopus:85076704383
- 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
- 2024-03-04 11:09:31
@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}},
keywords = {{C-galactosyl; Galectin-3; Inhibitor; Naphthamide; Selectivity}},
language = {{eng}},
month = {{12}},
number = {{24}},
publisher = {{MDPI AG}},
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}},
}