Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment

Abstract

Carbohydrate–receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered “undruggable”, meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate–receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate–receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteinsincluding flexibility, cooperativity, and multivalencyinto SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

“…One of the challenges in finding such conformers is the complex conformational space of flexible molecular complexes that has to be searched using sampling algorithms. Such methods, however, are rarely employed in the modeling of carbohydrate receptors, which hinders our understanding of interactions that drive the carbohydrate recognition [37] . To overcome this challenge and locate the lowest‐energy conformers, we adopted a cascade‐based approach that was described in our previous work [38a] .…”

“…Natural GBPs, however, do not necessarily follow this traditional ‘lock‐and‐key’ binding model, and the flexible Glc/Gal periplasmic binding protein, for example, achieves selectivity by accessing multivalent and cooperative binding modes that arise upon conformational rearrangement [36] . As such, these flexible GBPs suggest that a different paradigm may be more appropriate for the design of SCRs that are intended to bind non‐glucosidic carbohydrates, where structural flexibility is intentionally incorporated into the receptor structure [37] . To this end, our group has reported a series of noncovalent SCRs based upon a biaryl framework with four pendant heterocyclic arms appended to the core by secondary amine linkages [37–38] .…”

“…As such, these flexible GBPs suggest that a different paradigm may be more appropriate for the design of SCRs that are intended to bind non‐glucosidic carbohydrates, where structural flexibility is intentionally incorporated into the receptor structure [37] . To this end, our group has reported a series of noncovalent SCRs based upon a biaryl framework with four pendant heterocyclic arms appended to the core by secondary amine linkages [37–38] . These molecules are intended to bind glycan targets via H‐bonding and C−H⋅⋅⋅π interactions.…”

“…The binding of the first of these tetrapodal receptors, SCR001 , with monosaccharides was studied in CDCl 3 and CH 2 Cl 2 , which were chosen as solvents to maximize the strength of noncovalent interactions, and SCR001 showed a slight preference for mannosides [38b,c] . Since then, we have made a series of these tetrapodal SCRs that vary the nature of the heterocycle, the binding between the heterocycle and the biaryl core, and the receptor valency [37–38] . The result of these studies is a library of SCRs with varying binding affinities and selectivities.…”

State-of-the-Art of Nanodiagnostics and Nanotherapeutics against SARS-CoV-2

“…Accordingly, some clinical trials are being conducted using camostat and nafamostat against COVID-19. 277 Also, a variety of different drugs and approaches including protease inhibitor delivery using extracellular vesicles, 278 carbohydrate receptors as viral inhibitors, 279 and antiviral phytochemicals 280 have been suggested against SARS-CoV-2. Nevertheless, more investigations are required to find the certain and specific drug for COVID-19 therapy.…”