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      TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

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          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.

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          Most cited references 155

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          MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4

          Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.
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            A semiempirical free energy force field with charge-based desolvation.

            The authors describe the development and testing of a semiempirical free energy force field for use in AutoDock4 and similar grid-based docking methods. The force field is based on a comprehensive thermodynamic model that allows incorporation of intramolecular energies into the predicted free energy of binding. It also incorporates a charge-based method for evaluation of desolvation designed to use a typical set of atom types. The method has been calibrated on a set of 188 diverse protein-ligand complexes of known structure and binding energy, and tested on a set of 100 complexes of ligands with retroviral proteases. The force field shows improvement in redocking simulations over the previous AutoDock3 force field.
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              Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.

               Ook Yoo,  B. Park,  In Je Kim (2007)
              TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                04 October 2017
                December 2017
                : 5
                : 4
                Affiliations
                [1 ]Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, Russia; kvsivak@ 123456gmail.com (K.V.S.); drugs_safety@ 123456mail.ru (T.N.S.-L.)
                [2 ]Laboratory of Bioinformatics, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia; yuri.porozov@ 123456gmail.com
                [3 ]Department of Pharmacology, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia; tchoubarov@ 123456mail.ru
                [4 ]Laboratory of Bioinformatics, ITMO University, 49 Kronverkskiy Pr., Saint Petersburg 197101, Russia
                [5 ]Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy
                Author notes
                [* ]Correspondence: nnkuzmich@ 123456gmail.com (N.N.K.); Tel.: +7-921-3491-750 (N.N.K.); francesco.peri@ 123456unimib.it (F.P.); Tel.: +39-026-448-3453 (F.P.); Fax: +7-812-499-15-15 (N.N.K.)
                Article
                vaccines-05-00034
                10.3390/vaccines5040034
                5748601
                28976923
                7a819f9c-02d5-4f36-8323-07e666905721
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                tlr4, sepsis, lps, cd14, md-2, in vivo studies, pamp, damp

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