Targeting the CRD F-face of Human Galectin-3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative.

Autor: Miller MC; Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA., Zheng Y; School of Life Science, Northeast Normal University, 130024, Changchun, People's Republic of China., Suylen D; Department of Biochemistry and CARIM, Maastricht University, 6229HX, Maastricht, The Netherlands., Ippel H; Department of Biochemistry and CARIM, Maastricht University, 6229HX, Maastricht, The Netherlands., Cañada FJ; NMR and Molecular Recognition Group, Centro de Investigaciones Biológicas Margarita Salas (CSIC), C/Ramiro de Maeztu 9, 28040, Madrid, Spain., Berbís MA; NMR and Molecular Recognition Group, Centro de Investigaciones Biológicas Margarita Salas (CSIC), C/Ramiro de Maeztu 9, 28040, Madrid, Spain., Jiménez-Barbero J; NMR and Molecular Recognition Group, Centro de Investigaciones Biológicas Margarita Salas (CSIC), C/Ramiro de Maeztu 9, 28040, Madrid, Spain.; CIC bioGUNE, Bizkaia Technological Park, Building 801 A, 48160, Derio, Spain.; Ikerbasque, Basque Foundation for Science, 28009, Bilbao, Spain., Tai G; School of Life Science, Northeast Normal University, 130024, Changchun, People's Republic of China., Gabius HJ; Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximillians-University, 80539, Munich, Germany., Mayo KH; Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Feb 17; Vol. 16 (4), pp. 713-723. Date of Electronic Publication: 2020 Dec 01.
DOI: 10.1002/cmdc.202000742
Abstrakt: Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin-1, a β-galactoside-binding lectin. To assess the affinity profile of PTX008 for galectins, we used 15 N, 1 H HSQC NMR spectroscopy to show that PTX008 also binds to galectin-3 (Gal-3), albeit more weakly. We identified the contact site for PTX008 on the F-face of the Gal-3 carbohydrate recognition domain. STD NMR revealed that the hydrophobic phenyl ring crown of the calixarene is the binding epitope. With this information, we performed molecular modeling of the complex to assist in improving the rather low affinity of PTX008 for Gal-3. By removing the N-dimethyl alkyl chain amide groups, we produced PTX013 whose reduced alkyl chain length and polar character led to an approximately eightfold stronger binding than PTX008. PTX013 also binds Gal-1 more strongly than PTX008, whereas neither interacts strongly, if at all, with Gal-7. In addition, PTX013, like PTX008, is an allosteric inhibitor of galectin binding to the canonical ligand lactose. This study broadens the scope for galectin targeting by calixarene-based compounds and opens the perspective for selective galectin blocking.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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