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Article

Selectively Modified Lactose and N-Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands †

by
Shuay Abdullayev
1,
Priyanka Kadav
2,
Purnima Bandyopadhyay
2,
Francisco Javier Medrano
3,
Gabriel A. Rabinovich
4,
Tarun K. Dam
2,
Antonio Romero
3,* and
René Roy
1,*
1
Glycosciences and Nanomaterials Laboratory, Université du Québec à Montréal, Succ. Centre-Ville, P.O. Box 8888, Montréal, QC H3C 3P8, Canada
2
Laboratory of Mechanistic Glycobiology, Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
3
Centro de Investigaciones Biológicas “Margarita Salas” (CIB), CSIC, E-28040 Madrid, Spain
4
Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428 Ciudad de Buenos Aires, Argentina
*
Authors to whom correspondence should be addressed.
†
Dedicated to the memory of Prof. Hans-Joachim Gabius.
Int. J. Mol. Sci. 2023, 24(4), 3718; https://doi.org/10.3390/ijms24043718
Submission received: 25 January 2023 / Revised: 7 February 2023 / Accepted: 9 February 2023 / Published: 13 February 2023
(This article belongs to the Collection Feature Papers in 'Macromolecules')
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Abstract

Galectins constitute a family of galactose-binding lectins overly expressed in the tumor microenvironment as well as in innate and adaptive immune cells, in inflammatory diseases. Lactose ((β-D-galactopyranosyl)-(1→4)-β-D-glucopyranose, Lac) and N-Acetyllactosamine (2-acetamido-2-deoxy-4-O-β-D-galactopyranosyl-D-glucopyranose, LacNAc) have been widely exploited as ligands for a wide range of galectins, sometimes with modest selectivity. Even though several chemical modifications at single positions of the sugar rings have been applied to these ligands, very few examples combined the simultaneous modifications at key positions known to increase both affinity and selectivity. We report herein combined modifications at the anomeric position, C-2, and O-3′ of each of the two sugars, resulting in a 3′-O-sulfated LacNAc analog having a Kd of 14.7 µM against human Gal-3 as measured by isothermal titration calorimetry (ITC). This represents a six-fold increase in affinity when compared to methyl β-D-lactoside having a Kd of 91 µM. The three best compounds contained sulfate groups at the O-3′ position of the galactoside moieties, which were perfectly in line with the observed highly cationic character of the human Gal-3 binding site shown by the co-crystal of one of the best candidates of the LacNAc series.
Keywords: galectin; lactoside; isothermal titration calorimetry (ITC); X-ray galectin; lactoside; isothermal titration calorimetry (ITC); X-ray

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MDPI and ACS Style

Abdullayev, S.; Kadav, P.; Bandyopadhyay, P.; Medrano, F.J.; Rabinovich, G.A.; Dam, T.K.; Romero, A.; Roy, R. Selectively Modified Lactose and N-Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands. Int. J. Mol. Sci. 2023, 24, 3718. https://doi.org/10.3390/ijms24043718

AMA Style

Abdullayev S, Kadav P, Bandyopadhyay P, Medrano FJ, Rabinovich GA, Dam TK, Romero A, Roy R. Selectively Modified Lactose and N-Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands. International Journal of Molecular Sciences. 2023; 24(4):3718. https://doi.org/10.3390/ijms24043718

Chicago/Turabian Style

Abdullayev, Shuay, Priyanka Kadav, Purnima Bandyopadhyay, Francisco Javier Medrano, Gabriel A. Rabinovich, Tarun K. Dam, Antonio Romero, and René Roy. 2023. "Selectively Modified Lactose and N-Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands" International Journal of Molecular Sciences 24, no. 4: 3718. https://doi.org/10.3390/ijms24043718

APA Style

Abdullayev, S., Kadav, P., Bandyopadhyay, P., Medrano, F. J., Rabinovich, G. A., Dam, T. K., Romero, A., & Roy, R. (2023). Selectively Modified Lactose and N-Acetyllactosamine Analogs at Three Key Positions to Afford Effective Galectin-3 Ligands. International Journal of Molecular Sciences, 24(4), 3718. https://doi.org/10.3390/ijms24043718

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