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Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain

Mahanti, Mukul LU ; Gummesson, Sofi ; Sundin, Anders LU ; Leffler, Hakon LU ; Zetterberg, Fredrik and Nilsson, Ulf J LU (2024) In Bioorganic & Medicinal Chemistry 116.
Abstract

Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-D-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and... (More)

Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-D-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N[sbnd]H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Galectin, Glycomimetic, Sulfonamide
in
Bioorganic & Medicinal Chemistry
volume
116
article number
117989
pages
8 pages
publisher
Elsevier
external identifiers
  • scopus:85208986265
  • pmid:39549501
ISSN
0968-0896
DOI
10.1016/j.bmc.2024.117989
language
English
LU publication?
yes
id
aa2e411c-6143-408b-8721-c8b68f0dbe00
date added to LUP
2024-11-21 17:40:41
date last changed
2025-10-25 13:17:58
@article{aa2e411c-6143-408b-8721-c8b68f0dbe00,
  abstract     = {{<p>Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-D-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N[sbnd]H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.</p>}},
  author       = {{Mahanti, Mukul and Gummesson, Sofi and Sundin, Anders and Leffler, Hakon and Zetterberg, Fredrik and Nilsson, Ulf J}},
  issn         = {{0968-0896}},
  keywords     = {{Galectin; Glycomimetic; Sulfonamide}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Elsevier}},
  series       = {{Bioorganic & Medicinal Chemistry}},
  title        = {{Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain}},
  url          = {{http://dx.doi.org/10.1016/j.bmc.2024.117989}},
  doi          = {{10.1016/j.bmc.2024.117989}},
  volume       = {{116}},
  year         = {{2024}},
}