Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors

Abstract

Natural glycosaminoglycans (GAGs) are arguably the most diverse collection of natural products. Unfortunately, this bounty of structures remains untapped. Decades of research has realized only one GAG-like synthetic, small-molecule drug, fondaparinux. This represents an abysmal output because GAGs present a frontier that few medicinal chemists, and even fewer pharmaceutical companies, dare to undertake. GAGs are heterogeneous, polymeric, polydisperse, highly water soluble, synthetically challenging, too rapidly cleared, and difficult to analyze. Additionally, GAG binding to proteins is not very selective and GAG-binding sites are shallow. This Perspective attempts to transform this negative view into a much more promising one by highlighting recent advances in GAG mimetics. The Perspective focuses on the principles used in the design/discovery of drug-like, synthetic, sulfated small molecules as allosteric modulators of coagulation factors, such as antithrombin, thrombin, and factor XIa. These principles will also aid the design/discovery of sulfated agents against cancer, inflammation, and microbial infection.

Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G

“…Benzofuran-based NSGMs-Although sulfated benzofuran NSGMs displayed modest IC50s (5.5 to >50 µM, Table 1), interesting insights can be derived in terms of CatG recognition. CatG is a strongly basic protease with a predicted pI of 12 [49] and a predominantly electropositive surface area (Figure 1). A priori, this implies a high probability of Benzofuran-based NSGMs-Although sulfated benzofuran NSGMs displayed modest IC 50 s (5.5 to >50 µM, Table 1), interesting insights can be derived in terms of CatG recognition.…”

“…A priori, this implies a high probability of Benzofuran-based NSGMs-Although sulfated benzofuran NSGMs displayed modest IC 50 s (5.5 to >50 µM, Table 1), interesting insights can be derived in terms of CatG recognition. CatG is a strongly basic protease with a predicted pI of 12 [49] and a predominantly electropositive surface area (Figure 1). A priori, this implies a high probability of binding to polyanionic species such as long chain GAGs.…”