New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63

We report on the synthesis and pharmacological properties of a new series of thrombin inhibitors derived from hirudin carboxyl-terminal fragments. Two (arylphosphono)phenylalanines, p-PO3H2-L-Phe1 and m-PO3H2-L-Tyr, and one (carboxymethyl)phenylalanine, p-CH2COOH-L-Phe, were prepared and incorporated into position 63 of the modified hirudin's C-terminal dodecapeptide using the Fmoc solid-phase synthesis strategy. Substitution by any one of the residues led to very active analogs which doubled the thrombin time at low micromolar concentration (Ctt2) in vitro (1 microM < Ctt2 < 3 microM) and potently increased the activated partial thromboplastin time (APTT) ex vivo. These compounds displayed a higher potency in vitro and a longer duration of action in vivo than both the corresponding sulfated or phosphorylated tyrosine counterparts.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Guanidinobenzoyl derivatives of the hirudin 54-65 dodecapeptide bearing phosphono- or carboxymethyl-phenylalanine at position 63 doubled thrombin time at 1-3 microM in vitro, prolonged APTT ex vivo and outlasted sulfated or phosphorylated tyrosine analogues in vivo.

Explore how this research connects to clinical practice

More peer-reviewed studies in Drug Development.

• Hirudotherapy in Medicine and Dentistry — Jha K et al. (2015)
• Leech therapy: a history — Hyson J (2005)
• Hirudins of the Asian medicinal leech, Hirudinaria manillensis: same same, but different — Lukas P et al. (2019)
• Transcriptomic analysis of the salivary gland of medicinal leech Hirudo nipponia — Lu Z et al. (2018)
• Molecular dynamic and pharmacological studies on protein-engineered hirudin variants of Hirudinaria manillensis and Hirudo medicinalis — Sun Y et al. (2022)
• Cell-free synthesis of the hirudin variant 1 of the blood-sucking leech Hirudo medicinalis — Wüstenhagen D et al. (2020)
• Hirudin variants production by genetic engineered microbial factory — Zhang J, Lan N (2018)
• Hirudin in heparin-induced thrombocytopenia — Lubenow N, Greinacher A (2002)
• Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis — Han J et al. (2023)
• Hirudin as alternative anticoagulant--a historical review — Markwardt F (2002)

Browse all ASH-analysed research →