Rational Design of TLR4/MD-2 Complex Ligands for Innate Imune System Modulation

• Grant number: 13/10587-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2013
• End date: September 30, 2015
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Silvana Giuliatti
• Grantee: Evandro Pizeta Semighini
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Sepsis and septic shock are pathologies characterized by an intense systemic immune response, leading around 50% of the patients to death and, until now, doesn't have an adequate therapy. About 40% of all cases of sepsis results of a Gram-negative infection response. The LPS is a component of the cell membrane of these bacteria, and is the antigen that causes the immune response. The TLR4/MD-2 complex is an Innate Immune System component, and it's responsible for the body's response to the presence of LPS, whether integrated or not the bacteria. This system is also involved in other pathological processes such as chronic pain, some types of cancer and vaccine immunization. The LPS has a general structure common to most Gram-negative bacteria, but some of them do not trigger the aggressive immune response that leads to sepsis. This information leaded the development of the TLR4/MD-2 inhibitors, which prevents the excessive systemic immune response characteristic of sepsis. This project aims virtual screening assays in large databases of chemical structures followed by the evaluation of the computational results, both in silico methodologies, to develop new competitive inhibitors of LPS to the TLR4/MD-2 system. These inhibitors will be further evaluated in vitro as alternatives for the treatment of sepsis.