Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals.

Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms.

Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of ß-amyloid aggregation and inflammation mediated neurotoxicity.

A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer's disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Aß(1-42) self-aggregation. Among them, compound 7q exhibited the best inhibition of Aß(1-42) self-aggregation (59.11% at 20 µM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1ß and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC50 values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment.

[Pharmacophore identification of novel dual-target compounds targeting AChE and PARP-1].

Multi-target drugs attract increasing attentions for the therapy of complicated neurodegenerative diseases. In this study, a computer-assisted strategy was applied to search for multi-target compounds by the pharmacophore matching. This strategy has been successfully used to design dual-target inhibitor models against both the acetylcholinesterase (AChE) and poly (ADP-ribose) polymerase-1 (PARP-1). Based on two pharmacophore models matching and physicochemical properties filtering, one hit was identified which could inhibit AChE with IC50 value of (0.337 +/- 0.052) micromol x L(-1) and PARP-1 by 24.6% at 1 micromol x L(-1).

Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, ß-amyloid aggregation and Ca²âº overload.

In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aß(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease.

[The design of muti-target antitumor drugs affecting on FTase and Raf-1 kinase].

Ras/Raf/MEK/ERK singal transduction plays an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolism. This investigation focused on this signal pathway and chose farnesyl transferase (FTase) as the main target and Raf-1 kinase as the second target. A lot of compounds were selected to construct the pharmacophore models of farnesyl transferase inhibitors (FTIs) and Raf-1 kinase inhibitors by using computer-aided drug design (CADD). The pharmacophore of FTIs is constituted by a hydrogen bonding acceptor, an aromatic ring, a positive ionizable and two hydrophobic regions; the pharmacophore of Raf-1 kinase is constituted by a hydrogen donor, a hydrogen acceptor, a hydrophobic regions and an aromatic ring. There are some similarities between the two pharmacophores. After analysis of the constructions of these two pharmacophores, some new aminomethylbenzoic acid derivatives with good forecasting activity against both of FTase and Raf-1 kinase were designed with these new pharmacophore models.

[The multi-target drugs and their design].

The reduce of bioactivity and augment of the side effect of single-target drugs is generated by the multi-factorial properties of the pathogenesis of disease, which could be solved by the multi-target drugs. The problems and its solution of the design of the multi-target drugs were discussed in this paper, at the same time, the design of the multi-target drugs by pharmacophore model method is presented.

[Progress in the study of antitumor drug targeting on the Ras signaling pathway].

Ras signaling pathway is closely related to the formation and growth of tumor. Currently, targeting on this signaling pathway is a hot research point for the design and development of anticancer drugs. In this paper, Ras protein as well as its related targets and inhibitors in signaling pathway were reviewed. It is expected to give research-related reference materials for the design of new anticancer drugs.

[Pharmacophore model of integrin alphavbeta3 antagonists].

In order to generate a pharmacophore model of integrin alphavbeta3 receptor antagonists and design lead compounds which have potent and selective activity against alphavbeta3 receptor with the help of this model. Thirty compounds (four categories) with highly inhibitory activity against the integrin alphavbeta3 receptor (IC50 < 110 nmol x L(-1)), amide, piperazine, piperidine, gamma-valerolactam as the intermediate junction, separately, were selected as a training set to construct a three-dimensional pharmacophore models of integrin alphavbeta3 receptor antagonists with the Catalyst software. The best pharmacophore model of integrin alphavbeta3 receptor antagonists with RMS = 0.73, Correl = 0.90, Weight = 1.17, Config = 14.00 is found out, which consisting of four features: a neg ionizable core (NI), two aliphatic hydrophobic core (HP) and an aromatic ring center (RA). Some new and easily obtained compounds with fine ADME properties and highly potent activity against alphavbeta3 receptor were designed with the new pharmacophore models.

Construction of the pharmacophore model of acetylcholinesterase inhibitor.

Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight = 3.29, RMS = 0.53, total cost-null cost = 62.75, Correl = 0.93, Config = 19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.

[Construction of pharmacophore model of PARP-1 inhibitor].

To construct the pharmacophore model of the poly (ADP-ribose) polymerase-1 inhibitor and to investigate the possible inhibitory mechanisms, ten pharmacophore models of PARP-1 inhibitor were established from the training set of thirty-eight PARP-1 inhibitors with conformer analysis and pharmacophore mapping by using the Catalyst software. Based on the mechanism of action and the known structure-activity relationship of PARP-1 inhibitor, an optimal pharmacophore model including two hydrogen-bonding acceptors and two aromatic hydrophobic core was confirmed. The reliability of the optimal pharmacophore model is preferably with RMS = 0.46, Correl = 0.91, Weight = 2.06, and Config = 15.97. This pharmacophore model not only provided some information about the interaction between enzyme and compound, but also showed excellent forecast ability and contributes to design the PARP-1 inhibitors with undiscovered structure.

Short-term Pharmacological Inhibition of MyD88 Homodimerization by a Novel Inhibitor Promotes Robust Allograft Tolerance in Mouse Cardiac and Skin Transplantation.

BACKGROUND: Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. RESULTS: TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4CD25FoxP3 Regulatory T cells in recipient mice. CONCLUSIONS: Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs.

[The design and synthesis of 2-aminothiazole derivatives and their inhibitory activity on apoptosis].

AIM: To investigate the inhibitory effect of 2-aminothiazole derivatives on Neuro-cell apoptosis and QSAR. METHODS: The 2-aminothiazole derivatives were designed and synthesized based on the lead compound of PFT-alpha, the protective action of the compounds I and II against and their inhibitory action on PC12 cell apoptosis induced by H2O2 were determined by MTT method and FCM method. The QSAR equation was obtained from Cerius2-QSAR+ module. RESULTS: Eleven novel 2-aminothiazole Schiff base compounds (II) have been designed and synthesized. The structure of the compound II were characterized by IR, MS,1H NMR, 13C NMR. Their protective action against and the inhibitory action on PC12 cell apoptosis induced by H2O2 were found in this experiment. The optimal QSAR equation obtained from the Cerius2-QSAR+ module by using log (1/EC50) with corresponding descriptors is Activity = 6.947 68 - 0.088 72 x "LUMO" - 0.043 018 x "Alogp98" - 0.128 752 x "Rad0fGration" + 0.018 246 x "Dipole-mag". The correlation statistics parameters of the above equation are as follows: r2 = 0.970, F-test = 49. 149, r = 0. 985 and Lse = 0. 001. CONCLUSION: The 2-aminothiazole derivatives exhibited certain activity in inhibiting PC12 cell apoptosis induced by H2O2. Some compounds such as I-6, I-9 and II-6 have the dual activities, the protective action against and inhibitory action on PC12 cell apoptosis induced by H2O2. The QSAR equation indicated that it is favorable for enhance the activity of 2-aminothiazole derivatives by the reduction of "radius of gyration" and the energy of "LUMO" of the compounds.

Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.

The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.

Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer.

BACKGROUND: The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy. METHODS: We generated a MyD88 inhibitor (TJ-M2010-5), which was designed to bind to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. We utilized a mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer (CAC) in combination with TJ-M2010-5 administration to investigate the anti-inflammation-related cancer effect of MyD88 inhibitor in vivo. Data were analyzed with one-way and repeated measures analysis of variance. Differences in survival between groups were compared using the log rank test. All statistical tests were two-sided. RESULTS: TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-α, IL-6,G-CSF, MIP-1ß, TGF-ß1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD(+)4 T cells) in colon tissues of mice. CONCLUSIONS: Our findings suggest that TLR/MyD88 signaling may be a therapeutic target for CAC intervention and MyD88 inhibitors may be a promising therapeutic modality for treating patients with colitis or CAC.

ST09, a Novel Thioester Derivative of Tacrine, Alleviates Cognitive Deficits and Enhances Glucose Metabolism in Vascular Dementia Rats.

AIMS: Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto-tacrine derivatives with synergistic neuropharmacological profiles in vitro. METHODS: We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2-VO). RESULTS: ST09 and its active metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 significantly attenuated the 2-VO-induced impairment in spatial acquisition performance and inhibited the 2-VO-induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiols in 2-VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2-VO rats using functional imaging of (18) F-labeled fluoro-deoxyglucose (FDG) positron emission tomography (PET). CONCLUSIONS: ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton.

[Effect and mechanism of beta-L-D4A (a novel nucleoside analog) against hepatitis B virus].

OBJECTIVE: To explore the effect and the molecular targets of anti-hepatitis B virus (HBV) by beta-L-D4A in vitro. METHODS: 2.2.15 cells were cultured and treated with various concentrations of beta-L-D4A for 6 hours, then the effect of anti-HBV was examined by Southern blot and the replicating core particles from the cells were isolated. The endogenous polymerase reaction and activity gel experiment were performed to monitor the activities of the DNA polymerase and reverse transcriptase. RESULTS: The replication of HBV DNA was inhibited in a dose-dependent manner. The endogenous polymerase reaction showed both the two enzymatic activities were irreversibly inactivated in a concentration -dependent manner, with IC50 at 0.51 micromol/L and 0.55 micromol/L, respectively. But the activities of DNA polymerase and reverse transcriptase were found to remain active by activity gel with exogenous templates. CONCLUSIONS: The mechanism of inhibiting HBV replication by beta-L-D4A may be in that either the DNA replication priming is blocked or the elongation of DNA chain is terminated irreversibly.

Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases.

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases.

Design, synthesis, and cytoprotective effect of 2-aminothiazole analogues as potent poly(ADP-ribose) polymerase-1 inhibitors.

A series of novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors were designed within 2-aminothiazole analogues (4-10) based on a constructed three-dimensional pharmacophore model. After synthesis, the inhibitory effect on PARP-1 activity and the cytoprotective action of these compounds were tested and evaluated. Among them, compounds 4-6 and 10 appeared to be potent PARP-1 inhibitors with IC(50) values less than 1 microM, which had been perfectly predicted by pharmacophore model. These compounds proved to be highly potent against cell injury induced by H(2)O(2) and oxygen-glucose deprivation (OGD) in PC12 cells. These novel 2-aminothiazole analogues are potentially applicable as neuroprotective agents for the treatment of neurological diseases.