Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, ...CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.展开更多
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
文摘CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.
