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Newby, L. Kristin; Harrington, Robert A.; Bhapkar, Manjushri; Werf, Frans Van de; Hochman, Judith S.; Granger, Christopher B.; Simes, R. John; Davis, Catherine G.; Topol, Eric J.; Califf, Robert M.; Moliterno, David J.; Investigators, for the PARAGON A

doi:10.1023/a:1022062204490

Cited by 10 publications

(1 citation statement)

References 15 publications

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“…With this extremely narrow range, it is hard to slowly add more heparin to keep the patient in an anticoagulated state over the course of treatment, as even small additions could put patients over the safe upper range. It is likely that many patients treated with heparin are not optimally anticoagulated, at least not over the entire time period targeted. ,− …”

Section: Resultsmentioning

confidence: 99%

Development of Selective FXIa Inhibitors Based on Cyclic Peptides and Their Application for Safe Anticoagulation

Carle

Mukherjee

et al. 2021

J. Med. Chem.

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Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (K i = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3−0.7 IU/ mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.

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