On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein

Abstract

SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray of 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led to identification of only eight sequences as potent antagonists; results that were supported by detailed dual-filter computational studies. Competitive studies using the HS microarray suggested almost equivalent importance of IdoA2S–GlcNS6S and GlcNS3S structures, which were supported by affinity studies. Exhaustive virtual screening on a library of >93 000 sequences led to a novel pharmacophore with at least two 3- O -sulfated GlcN residues that can engineer unique selectivity in recognizing the RBD. This work puts forward the key structural motif in HS that should lead to potent and selective HS or HS-like agents against SARS-CoV-2.

Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

“…Together, the results presented in this study indicate that mutations that emerged in the new SARS-CoV-2 Omicron variant enhance the binding affinity of this variant to the host ACE2 receptor, which likely is an important driver of its increased transmissibility. However, it is important to note that SARS-CoV-2 besides ACE2 could also use other cellular receptors as a secondary binding way to target the host cells [19,[41][42][43]. Thus, it cannot be excluded that the changes that emerged in the Omicron viral spike could have an impact on the virus interaction with these secondary cellular receptors, additionally increasing the virus's ability to reach its target.…”

3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

“…It is now well recognized that most protein-binding Hp/HS sequences are tetra- to octa- saccharide long [12] , [14] , [15] , [33] , [34] , [35] . Hence, we chose hexameric sequences, which allow placing the 3OS group in the middle of the chain.…”

“…The recent release of the first draft of GAG interactome suggests more than 500 protein partners of these highly anionic polymers [9] . Among these, a number of proteins preferentially bind to 3- O -sulfate (3OS)-containing sequence(s) in Hp/HS including antithrombin [10] , fibroblast growth factor receptor [11] , glycoprotein D [12] , cyclophilin B [13] , neuropilin-1 [5] , heparin cofactor II [14] , tau glycoprotein [6] and spike glycoprotein [15] . Each of these sequences are distinct owing to the structural pattern flanking the 3OS group, which suggests the possibility of a “sulfation code”.…”

GlycoGrip: Cell Surface-Inspired Universal Sensor for Betacoronaviruses

“… 26 Gandhi and co-workers identified an otherwise unidentified site on the NTD. 36 Additionally, Boons and co-workers 29 and Desai and co-workers 55 have conducted extensive mappings of HS stereochemistry and sulfation patterns to identify key “heparin-like” motifs optimal for targeting the SARS-CoV-2 spike glycoprotein. Taken together, these works indicate that the structure of SARS-CoV-2 spike may have evolved to be uniquely tailored for binding glycocalyx GAGs.…”