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1.
Shock ; 61(6): 848-854, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38662595

ABSTRACT

ABSTRACT: Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 µg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.


Subject(s)
Polyphosphates , Thrombin , Wounds and Injuries , Humans , Thrombin/metabolism , Male , Adult , Wounds and Injuries/blood , Wounds and Injuries/drug therapy , Female , Middle Aged , Nucleic Acids/blood
2.
Adv Healthc Mater ; : e2400108, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38537246

ABSTRACT

Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin-binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.

3.
Nat Commun ; 14(1): 2177, 2023 04 26.
Article in English | MEDLINE | ID: mdl-37100783

ABSTRACT

Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Thrombosis , Mice , Animals , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Ligands , Thrombosis/drug therapy , Thrombosis/prevention & control , Anticoagulants/adverse effects , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Hemorrhage/drug therapy , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use
4.
Mol Pharm ; 19(6): 1853-1865, 2022 06 06.
Article in English | MEDLINE | ID: mdl-35500201

ABSTRACT

The polyanion, inorganic polyphosphate (polyP), is a procoagulant molecule which has become a promising therapeutic target in the development of antithrombotics. Neutralizing polyP's prothrombotic activity using polycationic inhibitors is one of the viable strategies to design new polyP inhibitors. However, in this approach, a fine balance between the electrostatic interaction of polyP and the inhibitor is needed. Any unprotected polycations are known to interact with negatively charged blood components, potentially resulting in platelet activation, cellular toxicity, and bleeding. Thus, designing potent polycationic polyP inhibitors with good biocompatibility is a major challenge. Building on our previous research on universal heparin reversal agent (UHRA), we report polyP inhibitors with a modified steric shield design. The molecular weight, number of cationic binding groups, and the length of the polyethylene glycol (PEG) chains were varied to arrive at the desired inhibitor. We studied two different PEG lengths (mPEG-750 versus mPEG-350) on the polyglycerol scaffold and investigated their influence on biocompatibility and polyP neutralization activity. The polyP inhibitor with mPEG-750 brush layer, mPEG750 UHRA-10, showed superior biocompatibility compared to its mPEG-350 analogs by a number of measured parameters without losing its neutralization activity. An increase in cationic binding groups (25 groups in mPEG750 UHRA-8 and 32 in mPEG750 UHRA-10 [HC]) did not alter the neutralization activity, which suggested that the mPEG-750 shield layer provides significant protection of cationic binding groups and thus helps to minimize unwanted nonspecific interactions. Furthermore, these modified polyP inhibitors are highly biocompatible compared to conventional polycations that have been previously used as polyP inhibitors (e.g., PAMAM dendrimers and polyethylenimine). Through this study, we demonstrated the importance of the design of steric shield toward highly biocompatible polyP inhibitors. This approach can be exploited in the design of highly biocompatible macromolecular inhibitors.


Subject(s)
Fibrinolytic Agents , Polyphosphates , Fibrinolytic Agents/pharmacology , Platelet Activation
5.
Biomacromolecules ; 21(7): 2595-2621, 2020 07 13.
Article in English | MEDLINE | ID: mdl-32497427

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.


Subject(s)
Blood Coagulation , Heparin , Anticoagulants/pharmacology , Hemorrhage , Heparin/pharmacology , Humans , Polyelectrolytes
6.
J Mater Chem B ; 5(47): 9249-9277, 2017 Dec 21.
Article in English | MEDLINE | ID: mdl-32264530

ABSTRACT

In the pursuit of dendrimer alternatives, hyperbranched polymers have found increasing interest from academia and industry in a broad range of fields due to their topological and synthetic advantages. Hyperbranched polyglycerol (HPG), as the name implies, is a hyperbranched polymer with about 50-65% dendrimeric structure. Due to its ease in synthesis, globular nature, versatility in terms of functionalization, and superb biocompatibility profiles HPG provides a promising class of materials suitable for numerous applications in nanomedicine and biomedical technologies. The structural features of HPG can be easily tailored by adopting different synthetic methodologies. In this review, we briefly explore the synthesis of HPGs starting from the traditional Lewis acid based approaches to recent advances including the development of high MW HPGs, biodegradable HPGs, co-block HPGs and sustainable or 'green' HPG synthesis. The robust history of HPG biocompatibility is extensively reviewed giving examples of both in vitro and in vivo models. In particular, HPG showed very minimal polymer accumulation in vital organs after intravenous injection compared to other polymers widely used for various biomedical applications. HPG is well tolerated in mice and rats, and has been found to be non-immunogenic to date. Due to its demonstrated safety profile and multifunctionality, HPG has been extensively studied for different biomedical applications including as macromolecular therapeutics, multivalent inhibitors/scavengers, in controlled drug delivery systems, in organ preservation, dialysis and cell surface engineering, as imaging agents and theranostics, in the development of anti-fouling surfaces and proteomics reagents. We highlight these applications along with its advantages. Finally, we conclude by providing a future prospective of HPG as one of the promising PEG alternatives with a great potential to enter clinical trials in the near future.

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