Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00619343" target="_blank" >RIV/61388963:_____/25:00619343 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10501296 RIV/00216208:11310/25:10501296

Výsledek na webu

<a href="https://doi.org/10.1039/D5MD00071H" target="_blank" >https://doi.org/10.1039/D5MD00071H</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/D5MD00071H" target="_blank" >10.1039/D5MD00071H</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors

Popis výsledku v původním jazyce

Influenza virus, an RNA virus of the Orthomyxoviridae family, is responsible for widespread seasonal epidemics that result in 3 to 5 million severe illnesses and more than half a million deaths annually. Given the persistent circulation of pandemic influenza variants and increasing resistance to available inhibitors, there is an urgent need for new antiviral drugs effective against various viral subtypes. Viral RNA-dependent RNA polymerase, essential for viral replication, has emerged as a promising drug target. The PA subunit with endonuclease function is especially interesting, as development of the highly potent baloxavir marboxil (Xofluza) validated its importance as a novel drug target. Flavonoids have long been studied for their anti-influenza activity but have only recently been recognized as endonuclease inhibitors. We previously identified luteolin and its glucoside derivate, orientin, as potent endonuclease inhibitors, with their binding illustrated by X-ray crystallography structures. Building on this, we employed a scaffold hopping approach based on the luteolin structure to design structurally distinct compounds that resemble the flavonoid scaffold. Using an AlphaScreen binding assay, we identified 33 as a submicromolar PA inhibitor with low toxicity. We solved the crystal structure of the PA endonuclease-binding pseudoflavonoid 36, which has similar structure and inhibitory potency to 33. Furthermore, we identified 24, 33, 34 and 36 as inhibitors of influenza polymerase in a minireplicon luciferase reporter assay, as well as inhibitors of live H1N1 virus infection in A549 human lung cells.

Název v anglickém jazyce

Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors

Popis výsledku anglicky

Influenza virus, an RNA virus of the Orthomyxoviridae family, is responsible for widespread seasonal epidemics that result in 3 to 5 million severe illnesses and more than half a million deaths annually. Given the persistent circulation of pandemic influenza variants and increasing resistance to available inhibitors, there is an urgent need for new antiviral drugs effective against various viral subtypes. Viral RNA-dependent RNA polymerase, essential for viral replication, has emerged as a promising drug target. The PA subunit with endonuclease function is especially interesting, as development of the highly potent baloxavir marboxil (Xofluza) validated its importance as a novel drug target. Flavonoids have long been studied for their anti-influenza activity but have only recently been recognized as endonuclease inhibitors. We previously identified luteolin and its glucoside derivate, orientin, as potent endonuclease inhibitors, with their binding illustrated by X-ray crystallography structures. Building on this, we employed a scaffold hopping approach based on the luteolin structure to design structurally distinct compounds that resemble the flavonoid scaffold. Using an AlphaScreen binding assay, we identified 33 as a submicromolar PA inhibitor with low toxicity. We solved the crystal structure of the PA endonuclease-binding pseudoflavonoid 36, which has similar structure and inhibitory potency to 33. Furthermore, we identified 24, 33, 34 and 36 as inhibitors of influenza polymerase in a minireplicon luciferase reporter assay, as well as inhibitors of live H1N1 virus infection in A549 human lung cells.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

RSC Medicinal Chemistry

ISSN

2632-8682

e-ISSN

2632-8682

Svazek periodika

16

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

19

Strana od-do

3030-3048

Kód UT WoS článku

001505669200001

EID výsledku v databázi Scopus

2-s2.0-105008013566