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Open AccessArticle

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

1
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, POB124, SE-22100 Lund, Sweden
2
SARomics Biostructures AB, Medicon Village, SE-223 63 Lund, Sweden
3
Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University, POB124, SE-22100 Lund, Sweden
4
Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden
5
Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b, Klinikgatan 28, 221 84 Lund, Sweden
*
Author to whom correspondence should be addressed.
These authors contributed equally and share first authorship.
Molecules 2019, 24(24), 4554; https://doi.org/10.3390/molecules24244554
Received: 5 November 2019 / Revised: 6 December 2019 / Accepted: 11 December 2019 / Published: 12 December 2019
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. View Full-Text
Keywords: galectin-3; inhibitor; selectivity; C-galactosyl; naphthamide galectin-3; inhibitor; selectivity; C-galactosyl; naphthamide
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Dahlqvist, A.; Mandal, S.; Peterson, K.; Håkansson, M.; Logan, D.T.; Zetterberg, F.R.; Leffler, H.; Nilsson, U.J. 3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3. Molecules 2019, 24, 4554.

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