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Rational design of true hirudin mimetics: synthesis and characterization of multisite-directed alpha-thrombin inhibitors.
J Med Chem. 1996 May 10; 39(10):2008-17.JM

Abstract

We describe here the design, synthesis, and activity of a novel class of alpha-thrombin inhibitors named hirunorms. They were rationally designed to interact through their N-terminal end with the alpha-thrombin active site in a nonsubstrate mode and to specifically bind the fibrinogen recognition exosite. An appropriate spacer that is able to properly orient the N-terminal end in the active site was also selected. This spacer allowed the size of the inhibitors to be reduced to about one-third of the amino acid residues in the hirudin sequence. Hirunorms specifically inhibit the amidolytic action of human alpha-thrombin toward a small chromogenic substrate. The most active compounds of the series, hirunorms IV and V, inhibit alpha-thrombin catalyzed hydrolysis of Tos-Gly-Pro-Arg-p-nitroanilide with K(i) = 0.09 and K(i) = 0.21 nM, respectively. Comparison of the anticoagulant properties of hirunorms, natural hirudin from the European leech Hirudo medicinalis, and the synthetic analog hirulog-1 revealed that hirunorm IV is about 10-fold and 3-fold more active, on a molar base, than hirudin and hirulog-1 in increasing the aPTT, PT, and TT of normal human plasma. The peculiar structure of hirunorms makes them stable to the amidolytic action of thrombin without the introduction of any peptide bond modification. These molecules display long-lasting activity in human plasma, due to the presence of several unnatural amino acids in susceptible positions. Hirunorms are potential candidates for injectable anticoagulants, due to their potency, specificity of action, long-lasting activity, and safety profiles.

Authors+Show Affiliations

Centro Interdipartimentale di Ricerca su Peptidi Bioattivi, Napoli, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8642559

Citation

Lombardi, A, et al. "Rational Design of True Hirudin Mimetics: Synthesis and Characterization of Multisite-directed Alpha-thrombin Inhibitors." Journal of Medicinal Chemistry, vol. 39, no. 10, 1996, pp. 2008-17.
Lombardi A, Nastri F, Della Morte R, et al. Rational design of true hirudin mimetics: synthesis and characterization of multisite-directed alpha-thrombin inhibitors. J Med Chem. 1996;39(10):2008-17.
Lombardi, A., Nastri, F., Della Morte, R., Rossi, A., De Rosa, A., Staiano, N., Pedone, C., & Pavone, V. (1996). Rational design of true hirudin mimetics: synthesis and characterization of multisite-directed alpha-thrombin inhibitors. Journal of Medicinal Chemistry, 39(10), 2008-17.
Lombardi A, et al. Rational Design of True Hirudin Mimetics: Synthesis and Characterization of Multisite-directed Alpha-thrombin Inhibitors. J Med Chem. 1996 May 10;39(10):2008-17. PubMed PMID: 8642559.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rational design of true hirudin mimetics: synthesis and characterization of multisite-directed alpha-thrombin inhibitors. AU - Lombardi,A, AU - Nastri,F, AU - Della Morte,R, AU - Rossi,A, AU - De Rosa,A, AU - Staiano,N, AU - Pedone,C, AU - Pavone,V, PY - 1996/5/10/pubmed PY - 1996/5/10/medline PY - 1996/5/10/entrez SP - 2008 EP - 17 JF - Journal of medicinal chemistry JO - J Med Chem VL - 39 IS - 10 N2 - We describe here the design, synthesis, and activity of a novel class of alpha-thrombin inhibitors named hirunorms. They were rationally designed to interact through their N-terminal end with the alpha-thrombin active site in a nonsubstrate mode and to specifically bind the fibrinogen recognition exosite. An appropriate spacer that is able to properly orient the N-terminal end in the active site was also selected. This spacer allowed the size of the inhibitors to be reduced to about one-third of the amino acid residues in the hirudin sequence. Hirunorms specifically inhibit the amidolytic action of human alpha-thrombin toward a small chromogenic substrate. The most active compounds of the series, hirunorms IV and V, inhibit alpha-thrombin catalyzed hydrolysis of Tos-Gly-Pro-Arg-p-nitroanilide with K(i) = 0.09 and K(i) = 0.21 nM, respectively. Comparison of the anticoagulant properties of hirunorms, natural hirudin from the European leech Hirudo medicinalis, and the synthetic analog hirulog-1 revealed that hirunorm IV is about 10-fold and 3-fold more active, on a molar base, than hirudin and hirulog-1 in increasing the aPTT, PT, and TT of normal human plasma. The peculiar structure of hirunorms makes them stable to the amidolytic action of thrombin without the introduction of any peptide bond modification. These molecules display long-lasting activity in human plasma, due to the presence of several unnatural amino acids in susceptible positions. Hirunorms are potential candidates for injectable anticoagulants, due to their potency, specificity of action, long-lasting activity, and safety profiles. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/8642559/Rational_design_of_true_hirudin_mimetics:_synthesis_and_characterization_of_multisite_directed_alpha_thrombin_inhibitors_ L2 - https://doi.org/10.1021/jm950898g DB - PRIME DP - Unbound Medicine ER -