Evaluation and Mechanistic Investigation of Human Milk Oligosaccharide against SARS-CoV-2
Weiyan Yu, Yan Li, Dongdong Liu, Yongliang Wang, Jianjun Li, Yuguang Du, George F. Gao, Zhimin Li, Yueqiang Xu, Jinhua Wei
Abstract
Four human milk oligosaccharides (HMOs), 3′-sialyllactose (3′-SL), 6′-sialyllactose (6′-SL), 2′-fucosyllactose (2′-FL), and 3-fucosyllactose (3-FL), were assessed for their possible antiviral activity against the SARS-CoV-2 spike receptor binding domain (RBD) in vitro . Among them, only 2′-FL/3-FL exhibited obvious antibinding activity against direct binding and trans -binding in competitive immunocytochemistry and enzyme-linked immunosorbent assays. The antiviral effects of 2′-FL/3-FL were further confirmed by pseudoviral assays with three SARS-Cov-2 mutants, with a stronger inhibition effect of 2′-FL than 3-FL. Then, 2′-FL/3-FL were studied with molecular docking and microscale thermophoresis analysis, showing that the binding sites of 2′-FL on RBD were involved in receptor binding, in addition to a tighter bond between them, thus enabling 2′-FL to be more effective than 3-FL. Moreover, the immunomodulation effect of 2′-FL was preliminary evaluated and confirmed in a human alveolus chip. These results would open up possible applications of 2′-FL for the prevention of SARS-CoV-2 infections by competitive binding inhibition.