Acylpolyamine Mygalin as a TLR4 Antagonist Based on Molecular Docking and In Vitro Analyses

Autor(es)

Espinoza-Culupu, Abraham ^{[1, 2]} ; Vazquez-Ramirez, Ricardo ^[3] ; Farfan-Lopez, Mariella ^[4] ; Mendes, Elizabeth ^[2] ; Notomi Sato, Maria ^[5] ; da Silva Junior, Pedro Ismael ^{[1, 6]} ; Borges, Monamaris Marques ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] USP IBu IPT, Interunits Grad Program Biotechnol, BR-01000000 Sao Paulo - Brazil

^[2] Butantan Inst, Bacteriol Lab, BR-01000000 Sao Paulo - Brazil

^[3] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 0016, DF - Mexico

^[4] Univ Nacl Mayor San Marcos, Microbiol Mol & Biotechnol Lab, Lima Dist 15081 - Peru

^[5] Univ Sao Paulo, Sch Med, Lab Dermatol & Immunodeficiencies, BR-01000000 Sao Paulo - Brazil

^[6] Butantan Inst, Lab Appl Toxinol LETA, BR-01000000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOMOLECULES; v. 10, n. 12 DEC 2020.
• Citações Web of Science: 0

Resumo

Toll-like receptors (TLRs) are transmembrane proteins that are key regulators of innate and adaptive immune responses, particularly TLR4, and they have been identified as potential drug targets for the treatment of disease. Several low-molecular-weight compounds are being considered as new drug targets for various applications, including as immune modulators. Mygalin, a 417 Da synthetic bis-acylpolyamine, is an analog of spermidine that has microbicidal activity. In this study, we investigated the effect of mygalin on the innate immune response based on a virtual screening (VS) and molecular docking analysis. Bone marrow-derived macrophages and the cell lines J774A.1 and RAW 264.7 stimulated with lipopolysaccharide (LPS) were used to confirm the data obtained in silico. Virtual screening and molecular docking suggested that mygalin binds to TLR4 via the protein myeloid differentiation factor 2 (MD-2) and LPS. Macrophages stimulated by mygalin plus LPS showed suppressed gene expression of tumor necrosis factor (TNF-alpha), interleukine 6 (IL-6), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibition of signaling protein p65 of the nuclear factor kappa B (NF-kappa B), resulting in decreased production of nitric oxide (NO) and TNF-alpha. These results indicate that mygalin has anti-inflammatory potential, being an attractive option to be explored. In addition, we reinforce the importance of virtual screening analysis to assist in the discovery of new drugs. (AU)

• Processo FAPESP: 13/11212-9 - Migalina: mecanismo imunomodulador e seu potencial no controle de infecções bacterianas
• Beneficiário: Monamaris Marques Borges
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs