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Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo.

ABSTRACT: Anticoagulant therapeutics are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent - heparin. Herein we report the first synthesis, characterization, and performance of sulfated poly-amido-saccharides (sulPASs) as heparin mimetics. sulPASs inhibit the intrinsic pathway of coagulation, specifically FXa and FXIa, as revealed by ex vivo human plasma clotting assays and serine protease inhibition assays. sulPASs activity positively correlates with molecular weight and degree of sulfation. Importantly, sulPASs are not degraded by heparanases and are non-hemolytic. In addition, their activity is reversed by protamine sulfate, unlike small molecule anticoagulants. In an in vivo murine model, sulPASs extend clotting time in a dose dependent manner with bleeding risk comparable to heparin. These findings support continued development of synthetic anticoagulants to address the clinical risks and shortages associated with heparin.

SUBMITTER: Varghese M

PROVIDER: S-EPMC8494039 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo.

Varghese Maria M Rokosh Rae S RS Haller Carolyn A CA Chin Stacy L SL Chen Jiaxuan J Dai Erbin E Xiao Ruiqing R Chaikof Elliot L EL Grinstaff Mark W MW

Chemical science 20210826 38

Anticoagulant therapeutics are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent - heparin. Herein we report the first synthesis, characterization, and performance of sulfated poly-amido-saccharides (sulPASs) as heparin mimetics. sulPASs inhibit the intrinsic pathway of coagulation, specifically FXa and FXIa, as revealed by ex vivo human plasma clotting assays and serine p ...[more]

PMID: 34703558

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Project description:Sulfated phenolic polymers have extensively been investigated as anticoagulant agents in view of their higher bioavailability and resistance to degradation compared to heparins, allowing for increased half-lives. In this frame, we report herein the preparation of sulfated derivatives of tyrosol, one of the most representative phenolic constituents of extra virgin olive oil, by different approaches. Mild sulfation of OligoTyr, a mixture of tyrosol oligomers, that has been reported to possess antioxidant properties and osteogenic activity, afforded OligoTyrS I in good yields. Elemental analysis, NMR, and MALDI-MS investigation provided evidence for an almost complete sulfation at the OH on the phenylethyl chain, leaving the phenolic OH free. Peroxidase/H2O2 oxidation of tyrosol sulfated at the alcoholic group (TyrS) also provided sulfated tyrosol oligomers (OligoTyrS II) that showed on structural analysis highly varied structural features arising likely from the addition of oxygen, derived from water or hydrogen peroxide, to the intermediate quinone methides and substantial involvement of the phenolic OH group in the oligomerization. In line with these characteristics, OligoTyrS I proved to be more active than OligoTyrS II as antioxidant in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assays and as anticoagulant in the classical clotting times, mainly in prolonging the activated partial thromboplastin time (APTT). After intraperitoneal administration in mice, OligoTyrS I was also able to significantly decrease the weight of an induced thrombus. Data from chromogenic coagulation assays showed that the anticoagulant effect of OligoTyrS I was not dependent on antithrombin or factor Xa and thrombin direct inhibition. These results clearly highlight how some structural facets of even closely related phenol polymers may be critical in dictating the anticoagulant activity, providing the key for the rationale design of active synthetic nonsaccharidic anticoagulant agents alternative to heparin.

Project description:In recent years, scientists have developed various biomaterials to remineralize human teeth to treat dentine hypersensitivity. Poly(amido amine) (PAMAM) dendrimers have become a research focus in this field. It has been demonstrated that PAMAM is able to create precipitates both on the surface of and within the dentinal tubules, however, there is little information about its effect on reducing dentine permeability in vitro. This study aimed to evaluate the in vitro effectiveness and stability of the fourth generation amine-terminated PAMAM on dentinal tubule occlusion, especially on dentine permeability. Sodium fluoride (NaF), which has been widely used as a desensitizing agent, is regarded as positive control. Demineralized sensitive dentine samples were coated with PAMAM or sodium fluoride solutions and soaked in artificial saliva (AS) at 37 °C for different periods. Four weeks later, samples in each group were then equally split into two subgroups for testing using a brushing challenge and an acid challenge. Dentine permeability of each specimen was measured before and after each challenge using a fluid filtration system. Dentine morphology and surface deposits were characterized by scanning electron microscope (SEM) and analyzed with Image-Pro Plus software. Data were evaluated through multifactorial ANOVA with repeated measures and pair-wise comparisons at a level of 5%. The results showed that PAMAM and NaF significantly reduced dentine permeability to 25.1% and 20.7%. Both of them created precipitates on dentine surfaces after AS immersion for 28 days. PAMAM-induced biomineralization not only on dentine surfaces, but also deeper in dentinal tubules, significantly reduced dentine permeability. Moreover, PAMAM-induced biomineralization elicited excellent stable occlusion effects after acid challenge. In conclusion, PAMAM demonstrated a strong ability to resist acid and showed great potential to be used in the treatment of dentine hypersensitivity in future.

Dataset Information

Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo.

Publications

Sulfated poly-amido-saccharides (sulPASs) are anticoagulants <i>in vitro</i> and <i>in vivo</i>.

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