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Publication Abstract from PubMed

Galectin-3 (Gal-3), a beta-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.

Molecular mechanism of interspecies differences in the binding affinity of TD139 to Galectin-3.,Kumar A, Paul M, Panda M, Jayaram S, Kalidindi N, Sale H, Vetrichelvan M, Gupta A, Mathur A, Beno B, Regueiro-Ren A, Cheng D, Ramarao M, Ghosh K Glycobiology. 2021 Nov 18;31(10):1390-1400. doi: 10.1093/glycob/cwab072. PMID:34228782^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.