| Autor: |
Jiang P; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China., Zhang C; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China., Wang H; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China., Li P; Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China., Du X; Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China., Wang Y; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China., Lyukmanova E; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 119997, Russia.; Biological Department, Shenzhen MSU-BIT University, Shenzhen 518172, China., Lin C; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China., Wang X; Laboratory of Chemical Biology, , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China.; Beijing National Laboratory for Molecular Sciences, Beijing 100190, China. |
| Abstrakt: |
Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling. |
