The branched sugars are ubiquitous in cells, decorating proteins to mediate numerous biological functions. As a result, their dysregulation can cause disease. Adam Braunschweig<\/a> at the Advanced Science Research Center at the CUNY Graduate Center and colleagues initially set out to develop glycan inhibitors to control cellular processes involved in ailments like cancer. But they soon realized that viruses, which use the sugars to bind to host cells<\/a>, would be the perfect proof of concept for the compounds.<\/p>\n The approach differs from other attempts to block glycans because it largely ignores a common molecular binding principle developed by Nobel Prize\u2013winner Donald J. Cram<\/a>: that host molecules should be rigid and preorganized<\/a> so they don\u2019t pay an entropic penalty that makes binding less favorable.<\/p>\n \u201cI didn\u2019t do my PhD in carbohydrate chemistry, which is probably the only reason why I decided to go into it. I was ignorant,\u201d Braunschweig says. But not having preconceived notions allowed Braunschweig to explore flexible organizations for synthetic carbohydrate receptors (SCRs) that take the entropic penalty when they glom on to glycans.<\/p>\n When sugars differ only by the orientation of only a couple of hydroxyl groups, rigid inhibitors struggle to bind, but flexibility allows the SCRs to adjust their shapes to a sugar\u2019s unique hydroxyl pattern. The receptors have a core made of two bound aromatic rings, with four extended arms that rotate and interact with hydroxyl and hydrogen groups on the sugars. This mimics natural sugar-binding proteins, which use many weak interactions to achieve strong bonds.<\/p>\n In a screen of 57 different SCRs against six replication-defective enveloped viruses from three different viral families and a nonenveloped glycosylated rotavirus, two candidates, SCR005 and SCR007, were found to reduce all virus levels.<\/p>\n In mice, the two compounds didn\u2019t have toxic effects even at high doses, and when the researchers gave the compounds to mice infected with SARS-CoV-2, they reduced mortality and disease severity.<\/p>\n The researchers were able to show that their most promising candidate, SCR007, directly binds N-glycans and that it selectively binds fucosylated N-glycans that have three or four branches\u2014an organization common in viruses. But Braunschweig says the team also found some evidence that the SCRs may be affecting cellular function independent of virus infection, and it will take more research to figure out exactly what\u2019s going on.<\/p>\n
\n Skeletal structure of N-glycan inhibitor SCR007.<\/p>\n