Sulfonated non‐saccharide molecules and human factor XIa: Enzyme inhibition and computational studies

Al‐Horani, Rami A.; Parsaeian, Elnaz; Mohammad, Mariam; Mottamal, Madhusoodanan

doi:10.1111/cbdd.14053

Cited by 7 publications

(17 citation statements)

References 82 publications

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“…The direct inhibition of FXIIa was assessed using a chromogenic substrate hydrolysis assay conducted under physiological conditions, specifically in a pH 7.4 Tris-HCl buffer at 37 °C, as previously documented. − In this assay, the hydrolysis of the substrate by FXIIa results in a linear increase in absorbance at a wavelength of 405 nm. The slope of the resulting line corresponds to the residual enzyme activity, and the change in residual enzyme activity, relative to the concentration of the inhibitor, is plotted and fitted using the logistic eq .…”

Section: Resultsmentioning

confidence: 99%

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

Woodland,

Thompson,

Lipford

et al. 2024

ACS Omega

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Factor XIIa (FXIIa) functions as a plasma serine protease within the contact activation pathway. Various animal models have indicated a substantial role for FXIIa in thromboembolic diseases. Interestingly, individuals and animals with FXII deficiency seem to maintain normal hemostasis. Consequently, inhibiting FXIIa could potentially offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks associated with the existing anticoagulants. Despite the potential, only a limited number of small molecule inhibitors targeting human FXIIa have been documented. Thus, we combined a small library of 32 triazole and triazole-like molecules to be evaluated for FXIIa inhibition by using a chromogenic substrate hydrolysis assay under physiological conditions. Initial screening at 200 μM involved 18 small molecules, revealing that 4 molecules inhibited FXIIa more than 20%. In addition to being the most potent inhibitor identified in the first round, inhibitor 8 also exhibited a substantial margin of selectivity against related serine proteases, including factors XIa, Xa, and IXa. However, the molecule also inhibited thrombin with a similar potency. It also prolonged the clotting time of human plasma, as was determined in the activated partial thromboplastin time and prothrombin time assays. Subsequent structure−activity relationship studies led to the identification of several inhibitors with submicromolar activity, among which inhibitor 22 appears to demonstrate significant selectivity not only over factors IXa, Xa, and XIa, but also over thrombin. In summary, this study introduces novel triazole-based small molecules, specifically compounds 8 and 22, identified as potent and selective inhibitors of human FXIIa. The aim is to advance these inhibitors for further development as anticoagulants to provide a more effective and safer approach to preventing and/or treating thromboembolic diseases.

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Section: Resultsmentioning

confidence: 99%

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

Woodland,

Thompson,

Lipford

et al. 2024

ACS Omega

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“…Interestingly, a rigid linker of 4,4′-(carbonylbis(azanediyl))bis( N -phenylbenzamide) connects two sulfated naphthalen-1-amines. Compound 81 , targeting the HBS in the catalytic domain, demonstrated good potency against human neutrophil elastase (HNE, IC 50 = 0.22 μM) and cathepsin G (IC 50 = 0.57 μM) associated with inflammation, implying that it may be useful in the treatment of inflammation-associated thrombosis via a synergistic effect against coagulation and inflammation . Furthermore, 81 did not show cellular toxicity against several cell lines, including CaCo-2, MCF-7, and HEK-293, at 90 μM, indicating that it is a potentially safe FXIa inhibitor.…”

Section: Design and Discovery Of Small-molecule Fxia Inhibitorsmentioning

confidence: 99%

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

et al. 2023

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Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure−activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.

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“…BTP was also found to inhibit FIX activation by FXIa, which relates better with physiological function. The second study evaluated a library of 18 sulfonated molecules that realized a FXIa inhibitor (Figure ) with 4.6 μM potency and >90% efficacy . The hexasulfonated analog demonstrated allosteric inhibition, as predicted on the basis of its high negative charge structure.…”

Section: Synthetic Sulfated Inhibitors Of Coagulation Factorsmentioning

confidence: 99%

“…The second study evaluated a library of 18 sulfonated molecules that realized a FXIa inhibitor (Figure 21) with 4.6 μM potency and >90% efficacy. 191 The hexasulfonated analog demonstrated allosteric inhibition, as predicted on the basis of its high negative charge structure. The advantage with phosphonate and sulfonate groups present in these molecules is their chemical and enzymatic stability.…”

Section: ■ Synthetic Sulfated Inhibitors Of Coagulation Factorsmentioning

confidence: 99%

“…Better anti-FXIa potency has been realized in two recent reports presenting phosphonate (ArPO 3 )- or sulfonate (ArSO 3 )-containing aryl urea analogs. , In the first report, a benzyl tetraphosphonate derivative (BTP, Figure ) was synthesized and found to inhibit human FXIa with a potency of 7.4 μM with reasonable selectivity (14-fold) against other coagulation factors. Interestingly, this molecule exhibited a sub-maximal efficacy of 68%, which suggests strong possibilities of deriving partial allosteric antagonists, as discussed in Figure .…”

Section: Synthetic Sulfated Inhibitors Of Coagulation Factorsmentioning

confidence: 99%

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

et al. 2023

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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.

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Sulfonated non‐saccharide molecules and human factor XIa: Enzyme inhibition and computational studies

Cited by 7 publications

References 82 publications

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

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

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