From Cancer to COVID‐19: A Perspective on Targeting Heparan Sulfate‐Protein Interactions

Abstract

Heparan sulfate (HS) is a complex, polyanionic polysaccharide ubiquitously expressed on cell surfaces and in the extracellular matrix. HS interacts with numerous proteins to mediate a vast array of biological and pathological processes. Inhibition of HS‐protein interactions is thus an attractive approach for new therapeutic development for cancer and infectious diseases, including COVID‐19; however, synthesis of well‐defined native HS oligosaccharides remains challenging. This has aroused significant interest in the development of HS mimetics which are more synthetically tractable and have fewer side effects, such as undesired anticoagulant activity. This account provides a perspective on the design and synthesis of different classes of HS mimetics with useful properties, and the development of various assays and molecular modelling tools to progress our understanding of their interactions with HS‐binding proteins.

Polymers Inspired by Heparin and Heparan Sulfate for Viral Targeting

“… 60 , 163 , 165 − 167 Results from studies with HP ultimately inspired the exploration of the oligosaccharide-based heparanase inhibitors Muparfostat (PI-88) and Pixatimod (PG545) (see Figure 3 ) as antiviral HS mimetics. 75 , 168 The oligosaccharide mixture Muparfostat (the chemical structure of the major component is shown in Figure 3 ) was shown to inhibit cell-to-cell spread of HSV. 169 Pixatimod, an advanced derivative of Muparfostat with improved features including a fully sulfated, isomerically pure oligosaccharide core and a hydrophobic cholestanol aglycone component, was shown to exhibit virucidal activity against HSV and protection against a variety of other viruses including SARS-CoV-2.…”

“… 169 Pixatimod, an advanced derivative of Muparfostat with improved features including a fully sulfated, isomerically pure oligosaccharide core and a hydrophobic cholestanol aglycone component, was shown to exhibit virucidal activity against HSV and protection against a variety of other viruses including SARS-CoV-2. 75 , 170 − 175 Similarly, another heparanase inhibitor Roneparstat (SST0001), a 15–25 kDa N -acetylated and glycol split version of heparin, 176 , 177 was shown to exhibit antiviral activity against SARS-CoV-2 as well as human T-lymphotropic virus 1 (HTLV-1) and HIV. 178 Notably, both Pixatimod and Roneparstat are in clinical trials and are being investigated for their immunomodulatory properties.…”

Synthesis of Four Orthogonally Protected Rare l-Hexose Thioglycosides from d-Mannose by C-5 and C-4 Epimerization

“…Apoptolidine A ( V ) macrolide antibiotic, isolated from Nocardiopsis species and used to initiate selective apoptosis of tumor cells, contains a 6-deoxy- l -glucose [ 14 , 15 , 16 ]. Furthermore, l -iduronic acid is a key component of the important mammalian glycosaminoglycans heparin, heparan sulfate, and dermatan sulfate [ 17 , 18 , 19 ].…”

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

“…This challenge has spurred the development of biomimetic analogs of HS and their study in molecular recognition processes. Several HS mimics have been reported in the literature. − However, they do not provide the structural variation needed to produce multiple functions like the native HS does. Thus, HS biomimetic analogs offer several advantages.…”