α-Glucan derivatives as selective blockers of aldolase A: Computer-aided structure optimization and the effects on HCC

Aldolase A (ALDOA) promotes hepatocellular carcinoma (HCC) growth and is a potential therapeutic target. A previous study found an α-D-glucan (α-D-(1,6)-Glcp-α-D-(1,4)-Glcp, 10.0:1.0), named HDPS-4II, that could specifically inhibit ALDOA but its activity was not high enough. In this study, the derivatives of α-D-glucan binding to ALDOA were optimized using molecular docking, and its sulfated modification demonstrated the highest affinity with ALDOA among sulfated, carboxylated, and aminated derivatives. Sulfated HDPS-4II and dextrans with different molecular weights (1000 Da, 3000 Da, and 4000 Da) were prepared. Using MST assay, 3-O-sulfated HDPS-4II (SHDPS-4II) and 1000 Da dextran (SDextran1) showed higher affinities to ALDOA with Kd of 1.83 μM and 85.04 μM, respectively. Furthermore, SHDPS-4II and SDextran1 markedly inhibited the proliferation of HCC cells both in vitro and in vivo by blocking ALDOA. These results demonstrate that sulfated modification of α-D-glucans could enhance their affinities with ALDOA and anti-HCC effects.