Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

Abstract

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects  chelation, clustering, and statistical rebinding  we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental–theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses.

Orchestrating Binding Interactions and the Emergence of Avidity Driven Therapeutics

“…In the current study, thermodynamic characterization of the highest affinity glycomimetic 2 by ITC revealed significant enthalpic stabilization that was partially compensated by entropic destabilization, when compared to its analogue 1 (Figure ). Notably, both glycomimetics are preorganized for chelation binding; however, 2 has increased ligand valency (Figure ).…”

“…Too flexible a linker, however, can incur significant entropic cost depending on the number of rotatable bonds in the linker that become frozen post binding. The findings of the current study also suggest the HIV-1 targeting conjugate and other avidity targeting conjugates for viral spike proteins may benefit from additional degenerate binding ligands and alternative topologies to increase statistical rebinding events.…”

“…The development of avidity targeting therapeutics is likely to accelerate in future drug discovery programs at both academic and industrial levels. High avidity binding inhibitors can in principle be efficiently developed using highly accessible lower affinity binding ligands like the simple disaccharides used in the current study . This can potentially avoid the extensive medicinal chemistry required to generate highly potent small molecule binding ligands.…”

“…This can potentially avoid the extensive medicinal chemistry required to generate highly potent small molecule binding ligands. In practice, however, this is highly nontrivial and requires careful design and biophysical experimentation as illustrated in the current body of work . As described above, multivalent ligands can benefit from multiple binding modes; however, this same binding event necessarily orders linker regions connecting the ligands, introducing conformational entropic cost.…”

“…To successfully develop such a therapeutic, several lower affinity binding ligands must be carefully arranged spatially, to maximize the probability of making one or several contacts with the target. In this issue of ACS Central Science , Fieschi, Bernardi, and co-workers reveal key design principles and validation strategies to guide the development of high avidity binding therapies. Importantly, their results provide a general framework to design therapeutics that use minimal binding ligands (i.e., minimal multivalency) to achieve high affinity binding to target lectins.…”