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Review
. 2017 Oct 4;5(4):34.
doi: 10.3390/vaccines5040034.

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

Nikolay N Kuzmich  1   2 , Konstantin V Sivak  3 , Vladimir N Chubarev  4 , Yuri B Porozov  5   6 , Tatiana N Savateeva-Lyubimova  7 , Francesco Peri  8
Affiliations
Review

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

Nikolay N Kuzmich et al. Vaccines (Basel). .

Abstract

Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.

Keywords: CD14; DAMP; LPS; MD-2; PAMP; TLR4; in vivo studies; sepsis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The lipopolysaccharide (LPS)/toll-Like Receptor 4 (TLR4) signaling pathway: the extracellular part (mediated by LPS-binding protein (LBP), cluster of differentiation 14 (CD14) and MD-2) and the intracellular part (myeloid differentiation primary response gene (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) branches).
Figure 2
Figure 2
Natural compounds with TLR4-antagonistic properties, tested in vivo on animal models of sepsis.
Figure 3
Figure 3
Artesunate and artemisinin.
Figure 4
Figure 4
The polyphenols corilagin (left) and epigallocatechin gallate (right).
Figure 5
Figure 5
Eritoran tetrasodium, PE-DTPA, TAK-242 (resatorvid) and its deuterated analogue.
Figure 6
Figure 6
Positively and negatively charged monosaccharides active as TLR4 antagonists
Figure 7
Figure 7
Chalcone L6H21, curcumin analogue L48H37 (upper row, from left to right), caffeic acid cyclohexylamide, general structure of synthesized cinnamamides, and the most active compound (from left to right, lower row).
Figure 8
Figure 8
Simvastatin, FC-98 and FC-99 (from left to right).
See this image and copyright information in PMC

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