For glycan interaction, HCoV-NL63 and MHV utilize heparan sulfate proteoglycans (HSPGs) as attachment enhancers [87,124]. Viruses recognize HSPGs as attachment molecules. In the spike (S) protein-deficient virions, the M protein recognizes HSPG. The S proteins generally bind to the viral cellular receptor. However, the M protein also acts as a receptor in the early step of HCoV-NL63 infection. The M membrane protein of HCoV-NL63 recognizes the attachment site of HSPGs. HCoV-NL63 M protein binds to HSPG for the initial attachment of virus to host cells and thereafter, the M and S proteins cooperate for virus entrance into the host cells [125]. HSPGs are glycosaminoglycan (GAG)-carrying proteins frequently used as a secondary receptor for viral entry. HSPGs are composed of covalent-bonded HS chains as a GAG form. The HS GAG linkage structure of tetrasaccharide exhibits GluAβ1,3GlcNAcα1,4Galβ1,3Galβ1,4Xylβ-O-serine. Glycosyltransferases involved in HS GAG synthesis include GlcAT-II (glucuronosyltransferase) and GlcNAcT-II (N-acetylglucosaminyltransferase II) for heparan sulfate synthesis (Figure 9). GAG is used as docking sites for virus interaction with the host cell surface. GAGs contain negatively charged N- and O-sulfated sugars [126]. The biosynthetic pathway and biologic roles in early embryogenic morphogenesis and vulval morphogenesis of HS and chondroitin sulfate GAG have been elucidated in Caenorhabditis elegans [127]. The negative charges mediate the interaction of GAGs and their ligands through electrostatic forces. Interaction of HSPG with ligands potentiates many virus infectious cycles. For examples, adeno-associated virus, human T cell lymphotropic virus type 1, human papilloma virus 16, herpes viruses, hepatitis B and C viruses, Kaposi’s sarcoma-associated herpesvirus, human papilloma viruses and Merkel cell polyoma virus recognize the HSPGs [128,129]. HSPGs increase virulence upon interaction with viral factors required for viral attachment and replication.