Novel, soluble 3-heteroaryl-substituted tanshinone mimics
attenuate the inflammatory response in murine macrophages

J 2024

Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages

FACEN, Elisa; Giulia ASSONI; Greta DONATI; Dalila PALADINO; Agata CARREIRA et. al.

Základní údaje

Originální název

Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages

Autoři

Vydání

Nature Scientific Reports, BERLIN, NATURE PORTFOLIO, 2024, 2045-2322

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.900

Kód RIV

RIV/00216224:14740/24:00138538

Organizační jednotka

Středoevropský technologický institut

DOI

https://doi.org/10.1038/s41598-024-73309-8

UT WoS

001339153400100

EID Scopus

2-s2.0-85206839848

Klíčová slova anglicky

ELAVL1; HuR; LPS; HuR inhibitors; Anti-inflammatory agents; Tanshinone mimics

Štítky

CF BIC, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 3. 6. 2025 13:15, Mgr. Eva Dubská

Anotace

V originále

The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR - 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b.

Návaznosti

EF18_046/0015974, projekt VaV

Název: Modernizace České infrastruktury pro integrativní strukturní biologii

90242, velká výzkumná infrastruktura

Název: CIISB III

Citovat

FACEN, Elisa; Giulia ASSONI; Greta DONATI; Dalila PALADINO; Agata CARREIRA; Isabelle BONOMO; La Pietra VALERIA; Roberta LOTTI; Josef HOUSER; Luca L FAVA; Pierfausto SENECI; Luciana MARINELLI; Daniela AROSIO a Alessandro PROVENZANI. Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages. Nature Scientific Reports. BERLIN: NATURE PORTFOLIO, 2024, roč. 14, č. 1, s. 1-19. ISSN 2045-2322. Dostupné z: https://doi.org/10.1038/s41598-024-73309-8.

@article{2468857,
   author = {Facen, Elisa and Assoni, Giulia and Donati, Greta and Paladino, Dalila and Carreira, Agata and Bonomo, Isabelle and Valeria, La Pietra and Lotti, Roberta and Houser, Josef and Fava, Luca L and Seneci, Pierfausto and Marinelli, Luciana and Arosio, Daniela and Provenzani, Alessandro},
   article_location = {BERLIN},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41598-024-73309-8},
   keywords = {ELAVL1; HuR; LPS; HuR inhibitors; Anti-inflammatory agents; Tanshinone mimics},
   language = {eng},
   issn = {2045-2322},
   journal = {Nature Scientific Reports},
   title = {Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages},
   url = {https://www.nature.com/articles/s41598-024-73309-8#citeas},
   volume = {14},
   year = {2024}
}

TY  - JOUR
ID  - 2468857
AU  - Facen, Elisa - Assoni, Giulia - Donati, Greta - Paladino, Dalila - Carreira, Agata - Bonomo, Isabelle - Valeria, La Pietra - Lotti, Roberta - Houser, Josef - Fava, Luca L - Seneci, Pierfausto - Marinelli, Luciana - Arosio, Daniela - Provenzani, Alessandro
PY  - 2024
TI  - Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages
JF  - Nature Scientific Reports
VL  - 14
IS  - 1
SP  - 1-19
EP  - 1-19
PB  - NATURE PORTFOLIO
SN  - 20452322
KW  - ELAVL1
KW  - HuR
KW  - LPS
KW  - HuR inhibitors
KW  - Anti-inflammatory agents
KW  - Tanshinone mimics
UR  - https://www.nature.com/articles/s41598-024-73309-8#citeas
N2  - The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR - 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b.
ER  -

FACEN, Elisa; Giulia ASSONI; Greta DONATI; Dalila PALADINO; Agata CARREIRA; Isabelle BONOMO; La Pietra VALERIA; Roberta LOTTI; Josef HOUSER; Luca L FAVA; Pierfausto SENECI; Luciana MARINELLI; Daniela AROSIO a Alessandro PROVENZANI. Novel, soluble 3-heteroaryl-substituted tanshinone mimics attenuate the inflammatory response in murine macrophages. \textit{Nature Scientific Reports}. BERLIN: NATURE PORTFOLIO, 2024, roč.~14, č.~1, s.~1-19. ISSN~2045-2322. Dostupné z: https://doi.org/10.1038/s41598-024-73309-8.

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