Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins—An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic

Abstract

Owing to the high mortality and the spread rate, the infectious disease caused by SARS-CoV-2 has become a major threat to public health and social economy, leading to over 70 million infections and 1. 6 million deaths to date. Since there are currently no effective therapeutic or widely available vaccines, it is of urgent need to look for new strategies for the treatment of SARS-CoV-2 infection diseases. Binding of a viral protein onto cell surface heparan sulfate (HS) is generally the first step in a cascade of interaction that is required for viral entry and the initiation of infection. Meanwhile, interactions of selectins and cytokines (e.g., IL-6 and TNF-α) with HS expressed on endothelial cells are crucial in controlling the recruitment of immune cells during inflammation. Thus, structurally defined heparin/HS and their mimetics might serve as potential drugs by competing with cell surface HS for the prevention of viral adhesion and modulation of inflammatory reaction. In this review, we will elaborate coronavirus invasion mechanisms and summarize the latest advances in HS–protein interactions, especially proteins relevant to the process of coronavirus infection and subsequent inflammation. Experimental and computational techniques involved will be emphasized.

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

“…A consistent amount of data supports the dependence of SARS-CoV-2 on HSPGs for an efficient infection. These data suggest that HSPGs serve as a co-receptor for the viral S protein interaction with the ACE2 entry receptor, thus contributing to viral internalization [ 66 , 109 , 110 , 129 , 132 , 225 ]. However, as HSPGs have been recognized as key inflammatory mediators in a variety of settings [ 6 , 226 , 227 ], they could play an important role in the regulation of the host cell immune response to SARS-CoV-2 infection.…”

“…Since 2020, a substantial number of studies have addressed the role and the mechanisms underlying the interaction between the viral envelope S protein of SARS-CoV-2 and the HSPGs that provide the first anchoring sites for the virus on the host cell surface [ 66 , 81 , 129 , 130 , 131 , 132 ]. It has been established that the binding of the S protein of SARS-CoV-2 to the host cells requires the engagement of both HS and ACE2 [ 131 ], thus suggesting that HSPGs act as a co-receptor for the S protein interaction with the ACE2 entry receptor [ 66 ].…”

“…For this purpose, the development of antibodies directed against HS, heparin/HS-based oligosaccharides, small HS mimetics, HS-degrading lyases, inhibitors of the HS biosynthetic machinery, and inhibitors of serine or cysteine proteases (i.e., cathepsins) involved in the viral endocytosis might prove useful therapeutic strategies to fight SARS-CoV-2 infection [ 9 , 20 , 38 , 66 , 75 , 81 , 132 , 139 , 174 , 175 , 176 , 177 , 178 ]. Table 3 reports some examples of HSPG-targeting therapeutics that have been proposed to be used alone or in combination with other drugs to block the infectious cycle of SARS-CoV-2.…”

Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

“…During virus entry, SARS-CoV-2 spike protein was demonstrated to interact with both cellular heparan sulfate and ACE2 [ 16 ]. Therefore, disrupting the interaction between heparan sulphate and spike protein by exogenous and competitive heparin mimetics could limit the SARS-CoV-2 virus entering the cell, resulting in suppression of the inflammatory responses [ 98 ]. Histamine has been shown capable of binding to heparan sulfate [ 99 , 100 ].…”

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

“…HS shares high structural similarity with heparin, but their functionalities are differentiated by the interactions with various proteins, such as proteases and protease inhibitors, cytokines and their respective receptors [114]. Recently, the preclusion of interaction between HS and S protein from heparin/HS mimetics has been proposed like anti-SARS-CoV-2 drugs [58]. Furthermore, Tandon et al [59] also suggested that intranasal administration of unfractionated heparin could be used as a prophylactic treatment of SARS-CoV-2.…”