Selection and Characterization of a DNA Aptamer Inhibiting Coagulation Factor XIa

Donkor, David A.; Bhakta, Varsha; Sheffield, William P.

doi:10.1016/j.tmrv.2016.05.004

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”

Section: Strategies To Inhibit Fximentioning

confidence: 99%

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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Abstract-The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development. Visual Overview-An online visual overview is available for this article. (Arterioscler Thromb Vasc Biol. 2018;38: 304-310.

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Section: Strategies To Inhibit Fximentioning

confidence: 99%

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Weitz

Fredenburgh

2018

ATVB

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“…FELIAP significantly inhibits plasma clotting and thrombin generation. FELIAP is the first FXIa-inhibiting aptamer and a lead compound to develop related aptamers [95]. Experiments of FXIa aptamer in animal models of both thrombosis and bleeding are being awaited.…”

Section: Aptamers Against Fximentioning

confidence: 99%

Aptamers for Thrombotic Diseases

Li¹,

Zhang²,

Zhao³

et al. 2021

Aptamers for Medical Applications

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Thrombosis is defined as a necessary physiological clotting process of hemostasis or harmful clinical events manifested as acute myocardial infarction (AMI), acute coronary syndromes (ACS), and thrombotic diseases. Nowadays, thrombotic diseases are the leading causes of morbidity and mortality which incur substantial healthcare expenditures worldwide. There are some shortcomings for current antithrombotics including bleeding potential, unpredictable pharmacokinetic and pharmacodynamic profiles, limited reversibility, and so on. Aptamers are short RNA or single-stranded DNA (ssDNA) oligonucleotides that fold into 3D conformations to recognize and bind their cognate targets. Aptamers are selected by an in vitro selection technique, i.e., Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Chemical synthesis renders aptamers both the characteristics of small molecule drugs and those of monoclonal antibodies. Some additional unique features, such as high specificity and affinity, flexible modification and stability, and lack of toxicity and immunogenicity, make aptamers hold great potential as a novel class of drugs and diagnostic reagents. In this review, we focus on the development of several aptamers and in particular those aptamers that have entered into clinical trials against anticoagulation factors and anti-adhesion molecules which are potential antithrombotics for thrombotic diseases.

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“…Very recently, Donkor et al. reported the selection and characterization of a DNA aptamer that inhibits FXIa . Aptamers are small sequences of nucleic acids that are capable of binding to a target protein with high affinity.…”

Section: Factor Xia (Fxia): An Emerging Protein Target For Anticoagulmentioning

confidence: 99%

Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding. Several inhibitors of FXI/FXIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides (ASOs), which ultimately reduce the hepatic biosynthesis of FXI, have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific FXI ASO effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of FXI/FXIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of FXI/FXIa inhibitors with the goal of advancing their development toward clinical use.

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Selection and Characterization of a DNA Aptamer Inhibiting Coagulation Factor XIa

Cited by 3 publications

References 29 publications

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Aptamers for Thrombotic Diseases

Recent advances in the discovery and development of factor XI/XIa inhibitors

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