Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock.

Abstract:

:Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Prasad KD,Trinath J,Biswas A,Sekar K,Balaji KN,Guru Row TN

doi

10.1038/srep07214

subject

Has Abstract

pub_date

2014-11-27 00:00:00

pages

7214

issn

2045-2322

pii

srep07214

journal_volume

4

pub_type

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