Počet záznamů: 1
Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors
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SYSNO ASEP 0556294 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors Tvůrce(i) Reiberger, R. (CZ)
Radilova, K. (CZ)
Král, M. (CZ)
Zima, V. (CZ)
Majer, P. (CZ)
Brynda, Jiří (UMG-J) RID
Dračínský, M. (CZ)
Konvalinka, J. (CZ)
Kožíšek, M. (CZ)
Machara, A. (CZ)Celkový počet autorů 10 Číslo článku 7735 Zdroj.dok. International Journal of Molecular Sciences. - : MDPI
Roč. 22, č. 14 (2021)Poč.str. 28 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. CH - Švýcarsko Klíč. slova bio-isosterism ; cross-coupling ; endonuclease inhibitor ; flavonoids ; influenza ; Mannich reaction ; RNA polymerase Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Biochemistry and molecular biology Způsob publikování Open access Institucionální podpora UMG-J - RVO:68378050 UT WOS 000676697900001 DOI 10.3390/ijms22147735 Anotace The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3 ',4 '-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 angstrom and 2.2 angstrom resolution, respectively. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2022 Elektronická adresa https://www.mdpi.com/1422-0067/22/14/7735
Počet záznamů: 1