Targeting Biological Polyanions in Blood: Strategies toward the Design of Therapeutics

Abstract

In this Review, we highlight well-described and emerging polyanions, and the way these molecules can be targeted in the design of potential therapeutics (synthetic and biologics) with applications in thrombosis and hemostasis. It is important to strike a balance between bleeding and clotting. In thrombosis, unwanted blood clots are formed in the lumen of a blood vessel, obstructing the flow of blood through the circulatory system. Over many years of research, several polyanionic biopolymers that can either impede (anticoagulant) or promote (procoagulant) blood clotting have been identified. Mediators impeding blood clotting, including polyanionic polysaccharides such as heparins and heparin mimics, are widely used as antithrombotics, although they impart adverse complications such as bleeding. Emerging synthetic polycations and well-described cationic proteins that are specifically designed to neutralize the biological activity of heparins to prevent bleeding complications are discussed. On the other hand, there is growing evidence that several polyanions bear a procoagulant nature in blood; polyphosphate (polyP), neutrophil extracellular traps (NETs), extracellular RNA, and cell-free DNA are shown to promote blood clotting. Recent research highlights the use of polycations and enzymes that either inhibit or cleave these procoagulant polyanions and demonstrates the proof-of-concept design of new antithrombotics without bleeding side effects. Additional studies have shown that some of these procoagulant polyanions can be used as a hemostat to prevent bleeding in an emergency. There are significant opportunities for chemists in the design of new inhibitors and agents with improved selectivity toward these biological polyanions, furthering the development of novel therapeutics.

Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor

“…This is a considerable advantage compared to current anticoagulant agents which all carry bleeding risk. We have previously examined various cationic molecules including PEI, PAMAM dendrimers, polymyxin, and poly­( l -lysine) as polyP inhibitors, , but significant toxicity issues are associated with these molecules . In most cases, the excessive positive charge generated from protonated primary amines at physiological pH generated undesirable toxicity, particularly altering blood coagulation and inducing cell/organ toxicity. , …”

“…Recent studies have investigated different approaches to inhibit polyP with the goal of developing new antithrombotic agents. − These include the use of polycationic polymers , and enzymes that cleave polyP . Cationic polymers including low-molecular-weight polyethylenimine (PEI), poly- l -lysine, and polyamidoamine (PAMAM) have been found to be potent polyP inhibitors in vitro and in vivo , among surveys of over 150,000 cationic compounds.…”

“…Cationic polymers including low-molecular-weight polyethylenimine (PEI), poly- l -lysine, and polyamidoamine (PAMAM) have been found to be potent polyP inhibitors in vitro and in vivo , among surveys of over 150,000 cationic compounds. However, these polymers are very toxic, − , likely due to the high density of cationic charges allowing for electrostatic neutralization of polyP albeit unwanted interactions with other negatively charged blood components and vasculature. Enzyme-based approaches were therefore explored, leading to the development of Escherichia coli exopolyphosphatase, a cytoplasmic polyphosphatase that catalyzes the hydrolysis of intracellular polyP.…”

Layer-by-Layer Cell Encapsulation for Drug Delivery: The History, Technique Basis, and Applications

“…Synthetic materials are manufactured in standard processes, so that the functional groups on them are highly consistent. Therefore, the application using synthetic polycations tends to become predictable and controllable [31].…”

Polyanions in Coagulation and Thrombosis: Focus on Polyphosphate and Neutrophils Extracellular Traps

“…Despite detailed information on polyP metabolism in yeast, not much is known about polyP regulation in mammals. The polymer is enriched in various 124,125 • vWF binds to isolated DNA in vitro, potentially acting as a linker for leukocyte adhesion to endothelial cells 126 • Accelerates the generation of FXIa and thrombin 127 • Amplifies thrombin-mediated activation of FXI 128 • Accelerates FV activation by FXa and thrombin 128 • Enhances the binding of platelets to von Willebrand factor 129 • Activates FXII 127 thereby also triggering inflammation via FXIIa-mediated activation of the kallikrein-kinin system 52 • Inactivates TFPI, abrogating its anticoagulant function 130 • Integrates into the fibrin clot, making it more resistant to fibrinolysis 131 • Binds extracellular histones and activates platelets 132 Cellular origin…”