Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure. (8th December 2014)

• Record Type: Journal Article
• Authors: Alam, Shahabuddin; Javor, Sacha; Degardin, Melissa; Ajami, Dariush; Rebek, Mitra; Kissner, Teri L.; Waag, David M.; Rebek, Julius; Saikh, Kamal U.
• Is Part Of: Chemical biology & drug design. Volume 86:Number 2(2015:Aug.)
• Page Start: 200
• Page End: 209
• Publication Date: 2014-12-08
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12477
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12477-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound <bold>1</bold> mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound <bold>1</bold> by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC<sub>50</sub> 1–50 <italic>μ</italic><sc>m</sc>) or LPS extracted from <italic>Francisella tularensis, Escherichia coli</italic>, or <italic>Burkholderia mallei</italic> (IC<sub>50</sub> 10–200 <italic>μ</italic><sc>m</sc>). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited <italic>Burkholderia mallei</italic> or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC<sub>50</sub> 10–30 <italic>μ</italic><sc>m</sc>). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.</p> </abstract>