Factor XIa

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Introduction

Anticoagulants are key substances for the prevention and/or treatment of thrombotic disorders, but every anticoagulant currently used clinically may cause serious adverse consequences, among which bleeding is the most common. Factor XIa (FXIa) is a key factor in the pathway of procoagulant signal amplification. Due to its low risk of bleeding, it has been used by scientists as the major target of anticoagulant drug discovery. At present, FXIa has become a promising drug target for effective anticoagulants with limited bleeding complications. The allosteric regulation of FXIa and the biosynthesis inhibition of FXI show unique characteristics in the mechanism. Although preliminary results have been obtained in patients undergoing knee arthroplasty, as with antisense oligonucleotides, in order to accelerate the pace of FXI/FXIa inhibitors entering the clinic, more significant progress should be achieved in terms of pharmacokinetics.

Figure 1. An overview of the waterfall model coagulation cascade (Al-Horani, R.A.; Desai, U.R. 2016)

FXIa: Structure, function, and a drug target

Human FXIa is a plasma serine protease, which is very different from other coagulation proteases. It is primarily synthesized by hepatocytes and circulates in the form of zymogen form (FXI) with a plasma concentration of approximately 30 nM. It is 160 kDa in size and is a homodimer linked by disulfide bonds, in which each monomer consists of 607 amino acid residues. Each monomer consists of a light chain (C-terminal domain) and a heavy chain (N-terminal domain). The former is a trypsin-like catalytic domain, while the latter has four 90- or 91- amino acid repeats, called the apple domain, labeled as A1 to A4. The active site of FXIa contains several subsites with substrate selectivity characteristics (S ₄ -S ₃ -S ₂ -S ₁ -S 1'-S 2'-S 3'-S 4'). In addition, the catalytic domain also has an anion binding site (or heparin-binding site).

The apple domain contains the FXI/FXIa binding sites for other macromolecules, including thrombin in A1 and high molecular weight kininogen (HK) in A2, FIX, platelet glycoprotein GPIb in A3, FXIIa in A4. The apple domain forms a disc structure, which is connected to the base of the catalytic domain to form a "cup and saucer" structure, which promotes the physiological functions of FXIa.

FXI is physiologically activated by FXIIa and thrombin, and can be automatically activated in the presence of polyanions (such as inorganic polyphosphate polymers). FXIa formed by FXI is mainly inhibited by plasma serpins, such as antithrombin and C1 inhibitors, etc.

Figure 2. Cartoon depiction of monomeric human FXI structure (Al-Horani, R.A.; Desai, U.R. 2016)

Expert opinion

In addition to having excellent pharmacodynamic characteristics, the "ideal" anticoagulant should: 1) have predictable pharmacokinetics; 2) reduce the effects on the liver (hepatotoxicity), bone (osteoporosis), and platelets (thrombocytopenia), low toxicity; 3) can be quickly reversed by the use of effective and inexpensive antidote; 4) does not require continuous monitoring, evaluation, and dose adjustment; 5) be safe in compromised patient populations such as pregnant women and cancer patients; 6) be available in relatively cheap and convenient oral or parenteral form. Although recent progress has been made in anticoagulant therapy, the clinical search for ideal anticoagulants continues.

All anticoagulants approved to date target thrombin and FXa, serine protease in the common coagulation pathway. In the past few decades, our understanding of the role of these factors in hemostasis and their impact on human genetic defects has made great progress, which provides convincing evidence for the inhibition of FXIa in the treatment and/or prevention of thromboembolism. Due to the emergence of various advanced structural information and molecular biology tools, many strategies targeting FXI/FXIa have been produced, the goal is to develop therapies that have no effect on hemostasis. These strategies have produced a large number of small and large molecules as FXI/FXIa inhibitors.

Although many advances have been made, FXI/FXIa inhibitors need further development work before they can enter the clinic, for example, the improvement of administration and delivery routes, and the research on pharmacokinetic characteristics. In addition, although different design strategies have been developed so far, the non-selectivity of active site peptidomimetic inhibitors still seems to be an ongoing problem.

Figure 3. Co-crystal structures for complexes of FXIa with 3 active site inhibitors showing different design approaches used (Al-Horani, R.A.; Desai, U.R. 2016)