Cell-surface heparan sulfate proteoglycans and related glycan receptors on airway epithelium (HSPG)

Cell-surface heparan sulfate proteoglycans (HSPGs) and related glycan receptors, such as sialic acids, are a diverse group of glycoproteins ubiquitously expressed on the airway epithelium that play a pivotal role in respiratory health and disease [MDPI, 2021]. These molecules, including syndecans and glypicans, consist of a core protein anchored to the cell membrane decorated with long, negatively charged heparan sulfate (HS) polysaccharide chains [NIH, 2021]. In the airway, they serve as essential attachment factors and co-receptors for numerous pathogens, such as SARS-CoV-2, respiratory syncytial virus (RSV), and various bacteria, by facilitating the initial docking and concentration of these agents on the epithelial surface [NIH, 2020; PLOS, 2021]. Beyond their role as attachment factors, HSPGs are critical regulators of cell signaling, acting as co-receptors for growth factors like FGF and VEGF, and modulating inflammatory responses by interacting with chemokines and cytokines [NIH, 2021]. In pathological conditions such as COVID-19, acute lung injury, or chronic obstructive pulmonary disease (COPD), the expression and sulfation patterns of these glycans are often altered, or they are shed into the extracellular space, contributing to tissue damage and viral spread [NIH, 2023]. Therapeutic targeting of these receptors involves the use of heparin mimetics (e.g., Pixatimod), small molecules (e.g., Mitoxantrone), or antibodies designed to block pathogen binding or inhibit HS-dependent endocytosis, offering a broad-spectrum approach to treating respiratory infections and inflammatory lung diseases [ACS, 2022; BioRxiv, 2020].

Other names

Cell-surface heparan sulfate proteoglycansHSPGsSyndecansGlypicansSialic acid receptorsMembrane-associated heparan sulfate proteoglycansAirway epithelial glycans

Competitive inhibition of viral attachment and entry by mimicking host cell glycans or blocking binding sites on the host cell surface; modulation of growth factor signaling and endocytosis.