Author/Editor     Anderluh, Marko; Sollner-Dolenc, Marija
Title     Antagonisti trombinskega receptorja
Translated title     Thrombin receptor antagonists
Type     članek
Source     Farm Vestn
Vol. and No.     Letnik 52, št. 4
Publication year     2001
Volume     str. 295-306
Language     slo
Abstract     The receptor of serine protease thrombin has been recently characterised. Its central role in thrombin-stimulated human platelet activation and vascular smooth muscle proliferation suggests receptor involvement in arterial thrombosis and atherosclerosis. Thrombin receptor has a novel mechanism of activation. The receptor, a member of seven-transmembrane domain receptors, is cleaved by thrombin at specific site on N-terminal extension at the outer membrane, and a newly exposed N-terminus acts as a »tethered ligand« to activate receptor itself. The development of thrombin receptor antagonists that may have value as therapeutic agents by specific inhibition of the cellular action of thrombin has been recognized, but such an agent has not thus far been realized. The lead compound with agonist activity was found to be N-terminal hexapeptide (Ser-Phe-Leu-Leu-Arg-Asn), which gave rational basis for development of peptide-based and nonpeptide thrombin receptor antagonists.
Summary     Receptorje serinske proteaze trombina so nedavno karakterizirali Vu in sodelavci. Osrednja vloga trombinskega receptorja v aktivaciji trombocitov stimulirani s trombinom in proliferaciji žilnih gladkih mišičnih celic kaže na vpletenost receptorja v arterijsko trombozo in aterosklerozo. Receptor sodi v družino transmembranskih receptorjev s sedmimi domenami. Aktivacija trombinskega receptorja poteče tako, da trombin cepi ekstracelularni N-terminalni konec receptorja, pri čemer se razgali okrnjen N-terminalni del, ta pa je sposoben avtoaktivacije preko vezave na ostali del receptorja. Antagonisti trombinskega receptorja so postali novo področje iskanja učinkovin, ki preprečujejo nastajanje krvnih strdkov. Čeprav zaenkrat {e ni terapevtsko uporabne učinkovine iz te skupine, pa si raziskovalci obetajo veliko s tem novim pristopom zaviranja strjevanja krvi. Kot spojina vodnica za načrtovanje antagonistov služi N-terminalni heksapeptid (Ser-Phe-Leu-Leu-Arg-Asn), ki nastane po proteazni aktivnosti trombina ob vezavi na receptor in ima agonistično aktivnost. Le-ta je ponudil racionalno osnovo za načrtovanje peptidnih in peptidomimetičnih antagonistov trombinskega receptorja .
Descriptors     RECEPTORS, THROMBIN
THROMBOSIS
ATHEROSCLEROSIS
SIGNAL TRANSDUCTION
AMINO ACID SEQUENCE
THIAZOLES