MOLECULAR MODELING, SYNTHESIS AND EVALUATION OF THE BIOLOGICAL ACTIVITY OF MODERN HETEROMEROUS PEPTIDES WITH IMIDAZO[4,5-Е]BENZO[1,2-C;3,4-C’]DIFUROXAN FRAGMENT AS NEW INHIBITORS OF PLATELET AGGREGATION

DOI: https://doi.org/None

А.А. Alexeev (1), M.I. Brylev (1), V.L. Korolev (1), D.S. Lotorev (1), А.U. Lizunov (2), N.I. Zaitseva (1), L.А. Pavlova (1), V.P. Ivshin (3) 1 -Sechenov First Moscow State Medical University, Trubetskaya, 8/2, Moscow, 119991, Russian Federation; 2 -Moscow Institute of Physics and Technology (State University), Institutskiy Pereulok, 9, Dolgoprudny, Moscow Region, 141700, Russian Federation; 3 -Mari State University, Lenina, 1, Yoshkar-Ola, Republic of Mari El, 424000, Russian Federation

Introduction. Cardiovascular diseases consistently occupy the first place among causes of death and disability in almost all developed countries. The main importance of this group of diseases have myocardial infarction. One of the causes of myocardial infarction is the formation of a blood clot. Well known that platelet aggregation is due to the binding of fibrinogen to GPIIb/IIIa receptors. The aim of the study. Synthesis of the new heteromeric peptides and evaluation their antithrombotic effect. Methods. Modeling the interaction of the protein integrin αIIb/β3 with peptides was performed using software «Algokomb». The modeled compounds have been made by solid-phase method of the strategy FastMoc 0,25 using the automatic peptide synthesizer ABI 433A Peptide Synthesizer (AppliedBiosystems, USA). The purification has done by preparative chromatography. The structure of the compounds has been confirmed by LCMS. The evaluation of the specificity of the synthesized compound has been made in vitro. Results. We applied software «Algokomb» to confirm the binding efficiency of some heteromerous peptides with imidazo[4,5-e]benzo[1,2c;3,4-c’]difuroxan fragment with GP IIb/IIIa receptor of platelets. The modeled compounds has been synthesized by the protocol of Fmoc-strategy. The evaluation of the specificity of the synthesized compounds has showed that antithrombotic effect of heteromerous peptides with imidazo[4,5-e] benzo[1,2-c;3,4-c’]difuroxan fragment higher than antithrombotic effect of peptides with standard amino acids. Conclusion. The most powerful antithrombotic peptide is Fur-Lys-His-Ala-Asp-Asp (А-2f) (IC50 1,52 мкМ).
Keywords: 
platelet GPIIb/IIIa receptors, inhibition of platelet aggregation, molecular modeling, imidazo[4, 5-e]benzo[1, 2-c, 3, 4-c’]difuroxans, heteromerous peptides, antithrombotic effect
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