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Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Nov;1862(11):1439-1450. doi: 10.1016/j.bbalip.2017.01.004. Epub 2017 Jan 17.

Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship.

Author information

1
Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD 21201, United States.
2
Institute of Marine & Environmental Technology, University of Maryland Center for Environmental Science, Baltimore, MD 21202, United States.
3
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
4
Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD 21201, United States. Electronic address: rkernst@umaryland.edu.

Abstract

Strategies utilizing Toll-like receptor 4 (TLR4) agonists for treatment of cancer, infectious diseases, and other targets report promising results. Potent TLR4 antagonists are also gaining attention as therapeutic leads. Though some principles for TLR4 modulation by lipid A have been described, a thorough understanding of the structure-activity relationship (SAR) is lacking. Only through a complete definition of lipid A-TLR4 SAR is it possible to predict TLR4 signaling effects of discrete lipid A structures, rendering them more pharmacologically relevant. A limited 'toolbox' of lipid A-modifying enzymes has been defined and is largely composed of enzymes from mesophile human and zoonotic pathogens. Expansion of this 'toolbox' will result from extending the search into lipid A biosynthesis and modification by bacteria living at the extremes. Here, we review the fundamentals of lipid A structure, advances in lipid A uses in TLR4 modulation, and the search for novel lipid A-modifying systems in extremophile bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.

KEYWORDS:

Lipid A modifying enzymes; Lipid A structure; Marine bacteria; TLR4 agonists; TLR4 antagonists; TLR4 immunomodulation

PMID:
28108356
PMCID:
PMC5513793
DOI:
10.1016/j.bbalip.2017.01.004
[Indexed for MEDLINE]
Free PMC Article

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