question: The COVID-19 pandemic caused by SARS-CoV-2, an enveloped, positive-sense RNA virus, has thwarted early attempts to repurpose current drugs, thereby necessitating a rigorous study of all pathways and mechanisms likely to yield, prevent and treat the disease (Drug Discov Today (2020) 25:1535-1544) While SARS-CoV-2 entry into host cells is known to involve viral surface spike glycoprotein (SgP) binding to the host cell membrane angiotensin-converting enzyme 2 (ACE2) receptor, heparan sulfate (HS) receptors are also beginning to be appreciated as involved in virus internalization The SgP is a homo-trimer consisting of S1 and S2 subunits, of which the former contains a receptor-binding domain (RBD) that recognizes ACE2 Application of the dual-filter, genetic algorithm-based computational screening strategy indicated selective recognition of the RBD by HS sequences over other glycosaminoglycans (GAGs) Likewise, exhaustive computational study of the SgP trimer indicates preferential interaction of HS with the RBD over plausible electropositive domains within the trimer More interestingly, the in silico studies suggested that the RBD favors binding to rare HS residues containing a defined set of sulfate groups in three-dimensional space Screening of a microarray carrying 24 HS sequences varying with regard to chain length, pattern and number of sulfate groups against S1 and RBD indicated that only 8 HS sequences had reasonable affinity for the RBD Interestingly, the recognition of these 8 HS sequences for S1 was much weaker possibly suggesting a role for the trimeric form of SgP versus its monomeric form Whereas the RBD preferred sequences with higher levels of sulfation, a distinct preference was noted for sequences containing a 3-O sulfate group This work presents a thorough insight into GAG-recognition of SARS-CoV-2 SgP and raises a strong possibility that GAG-or GAG mimetic-based antagonism of SgP-HS receptor interaction may yield a candidate drug