Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216208:11110/25:10501296 RIV/00216208:11310/25:10501296
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Beyond natural flavonoids: exploring bioisosterism in design and synthesis of influenza endonuclease inhibitors
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
RSC Medicinal Chemistry
ISSN
2632-8682
e-ISSN
2632-8682
Volume of the periodical
16
Issue of the periodical within the volume
7
Country of publishing house
GB - UNITED KINGDOM
Number of pages
19
Pages from-to
3030-3048
UT code for WoS article
001505669200001
EID of the result in the Scopus database
2-s2.0-105008013566