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Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Neal, MD and Jia, H and Eyer, B and Good, M and Guerriero, CJ and Sodhi, CP and Afrazi, A and Prindle, T and Ma, C and Branca, M and Ozolek, J and Brodsky, JL and Wipf, P and Hackam, DJ (2013) Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors. PLoS ONE, 8 (6).

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Abstract

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Neal, MDnealm@pitt.eduNEALM
Jia, H
Eyer, B
Good, Mmlg101@pitt.eduMLG101
Guerriero, CJcjg11@pitt.eduCJG110000-0002-1046-2300
Sodhi, CP
Afrazi, A
Prindle, T
Ma, Ccongrong@pitt.eduCONGRONG
Branca, M
Ozolek, Jjao2@pitt.eduJAO2
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Wipf, Ppwipf@pitt.eduPWIPF
Hackam, DJ
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorJeyaseelan, SamithambyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 12 June 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0065779
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Dietrich School of Arts and Sciences > Chemistry
School of Medicine > Pathology
School of Medicine > Pediatrics
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 15 Jul 2013 20:28
Last Modified: 02 Feb 2019 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/19197

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