TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis
Nikolay N. Kuzmich,
Konstantin V. Sivak,
Vladimir N. Chubarev,
Yuri B. Porozov,
Tatiana N. Savateeva-Lyubimova,
Francesco Peri
Affiliations
Nikolay N. Kuzmich
Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, Russia
Konstantin V. Sivak
Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, Russia
Vladimir N. Chubarev
Department of Pharmacology, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia
Yuri B. Porozov
Laboratory of Bioinformatics, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, Russia
Tatiana N. Savateeva-Lyubimova
Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, Russia
Francesco Peri
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy
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.
