Can glycans be targeted to stop viral diseases? Docking of viruses to host cells is often facilitated by the interactions between a glycan and a receptor. Because docking, which precedes viral infection and, ultimately, replication, is a necessary step in the virus life cycle, disrupting glycan-receptor interactions could mitigate the viral threat. The challenge with this approach, however, is that glycans are still considered “undruggable targets”, meaning no widely adopted therapeutic strategies exploit them as feasible target for drugs. In this contribution, I discuss recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that are able to sense structural differences of nonglycosidic carbohydrates. These SCRs are potent antivirals which show ability to inhibit Zika virus (ZIKV) infections in Vero cells at nanomolar concentrations. In order to understand their mode of action, we investigated using molecular simulations binding of the SCRs and N-glycans most commonly found on the surfaces of enveloped viruses - including Zika virus and SARS-CoV-2. Molecular dynamics reveal that, regardless of the glycan strucutre, SCRs consistently bind to the trimannosylchitobiose core of the N-glycan, which constitute the only conserved motif in these species. Importantly, the strength of the association depends on the weak interactions between the SCR recognition element – heterocycle rings - and the saccharides decorating the glycan antennae. Systematic variations in the SCR and glycan composition spell out relationships that could guide the design of SCRs to attain affinity and selectivity towards a chosen glycan target. These predictions of the receptors selectivity were tested against seven glycoforms of the SARS-CoV-2 spike glycoprotein trimer. The μs-scale simulations of the spike protein and SCRs show that the SCRs readily associate on the glycan portion of the glycoprotein. The resulting distribution of receptors on the protein surface not only depends on both the type of SCRs present and the composition of glycans but it also follows selectivity predicted by simulations of SCR●N-glycan complexes. The reported simulations show that glycans can be selectively targeted by SCRs and reclassification of glycans from “undruggable” to a viable antiviral target could open new avenues for developing novel treatments, diagnostics and sensors.

Binding of synthetic carbohydrate receptors to viral glycans

ACS Spring Meeting 2021

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