Telacebek (Q203): Vynára sa na obzore nové efektívne a bezpečné antituberkulotikum?

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Autoři: Ivan Malík; Jozef Čižmárik; Gustáv Kováč; Mária Pecháčová; Lucia Hudecova
Vyšlo v časopise: Čes. slov. Farm., 2021; 70, 164-171
Kategorie: Přehledy a odborná sdělení
doi: https://doi.org/https://doi.org/10.5817/CSF2021-5-164

Souhrn

Vysoká prevalencia rôznych foriem rezistentnej tuberkulózy (drug-resistant tuberculosis – DR-TB), vrátane multirezistentnej tuberkulózy (multidrug-resistant tuberculosis – MDR-TB) a extenzívne rezistentnej tuberkulózy (extensively drug-resistant tuberculosis – XDR-TB), ktoré sú zapríčinené rezistentnými patogénmi Mycobacterium tuberculosis, rezultuje do silnejúcej hrozby terapeutickej neefektívnosti antituberkulotík (anti-TB) prvej línie. Imperatívom je preto projekcia nových vysokoúčinných (syntetických) liečiv proti senzitívnym a aj rezistentným kmeňom mykobaktérií spôsobujúcim TB. V tomto kontexte je mimoriadne zaujímavé vedecky skúmať rôzne heterocykly ako perspektívne kľúčové štruktúry pre projekciu, vývoj a optimalizovanie takýchto anti-TB-liečiv. Telacebek (Q203; TCB), molekula obsahujúca imidazo[1,2-a]- pyridín-3-karboxamidový (IPA) štruktúrny motív, je považovaný za veľmi sľubnú anti-TB-substanciu, ktorá sa vyznačuje unikátnym mechanizmom pôsobenia. Táto zlúčenina blokuje oxidatívnu fosforyláciu mykobaktérií inhibíciou ich dýchacieho reťazca tak, že interferuje so špecifickou podjednotkou, cytochrómom b (QcrB), ktorý je súčasťou transmembránovej bc1 menachinol- cytochróm c oxidoreduktázy. Tento komplex je kľúčovým komponentom podieľajúcim sa na transmembránovom transporte elektrónov z menachinolu na ďalšiu špecifickú podjednotku, cytochróm c (QcrC). Schopnosť mykobaktérií syntetizovať adenozín-5´-trifosfát je potom limitovaná a súčasne sú významne obmedzené ich možnosti generovať energiu. TCB efektívne pôsobí proti susceptibilným, MDR- a aj XDR-kmeňom M. tuberculosis. V publikácii možno nájsť stručné vysvetlenie mechanizmu účinku zlúčenín obsahujúcich IPA-fragment a aj hodnotenie vzťahov medzi ich štruktúrou a anti-TB-aktivitou. Mimoriadna pozornosť je venovaná významu jednotlivých štruktúrnych častí TCB z pohľadu zachovania (alebo dokonca ďalšieho zlepšenia) výhodných farmakodynamických, farmakokinetických a/alebo toxikologických vlastností. Vysoká lipofilita TCB by mohla byť považovaná za jednu z kľúčových fyzikálno-chemických charakteristík, ktoré pozitívne ovplyvňujú anti-TB-pôsobenie tohto liečiva. V januári 2021 vstúpil TCB aj do fázy II klinického skúšania orientovaného na liečbu ochorenia COVID-19 (Coronavirus Disease-19), ktorého pôvodcom je koronavírus 2 vyvolávajúci ťažký akútny respiračný syndróm (Severe Acute Respiratory Syndrome Coronavirus 2).

Klíčová slova:

Mycobacterium tuberculosis – tuberkulóza rezistentná voči liečivám – imidazo[1,2-a]- pyridín-3-karboxamidy – telacebek (Q203) – dýchací reťazec

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