Structure-Activity Relationship Study of (E)-3-(6-Fluoro-1H-indol-3-Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) Against Metastatic Colorectal Cancers Resistant to Oxaliplatin.

Advanced metastatic colorectal cancer (mCRC) and the development of drug resistance to chemotherapy pose significant challenges in clinical settings. In previous studies, we have demonstrated the potent cytotoxic activity of (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) and related 30 derivatives against mCRC by targeting microtubules. In this study, we aimed to evaluate the efficacy of the 31 compounds and explore the structure-activity relationship (SAR) against oxaliplatin-resistant mCRC. We found that most of the derivatives showed high sensitivity toward the oxaliplatin-resistant HCT-116/L cells. Particularly, FC116 exhibited a better GI50 value against the resistant mCRC cell line, HCT-116/L, compared to standard therapies. We also observed a safer therapeutic window for FC116 and a synergistic effect when it was used in combination with oxaliplatin. Mechanistically, FC116 induced the G2/M phase arrest by downregulating cyclin B1 expression through its interaction with microtubules in resistant colorectal cancer cells. Furthermore, in vivo experiments demonstrated that FC116 significantly suppressed tumor growth, achieving a 78% reduction at a dose of 3 mg/kg, which was superior to the 40% reduction achieved by oxaliplatin treatment. Overall, our findings suggest that the indole-chalcone compound FC116 represents a promising lead for chemotherapy in oxaliplatin-resistant mCRC.

Pharmacokinetic, Tissue Distribution, Metabolite, and Toxicity Evaluation of the Matrine Derivative, (6aS, 10S, 11aR, 11bR, 11cS)-10-Methylaminododecahydro-3a, 7a-Diaza-benzo (de) Anthracene-8-thione.

MASM, a structurally modified derivative of matrine, exhibits superior efficacy in reducing inflammation and liver injury in rats when compared to matrine. This study aims to investigate the pharmacokinetic profile and acute toxicity of MASM. Pharmacokinetic results revealed that MASM exhibited rapid absorption, with a Tmax ranging from 0.21 ± 0.04 h to 1.31 ± 0.53 h, and was eliminated slowly, with a t1/2 of approximately 10 h regardless of the route of administration (intravenous, intraperitoneal, or intragastric). The absolute intragastric bioavailability of MASM in rats was determined to be 44.50%, which was significantly higher than that of matrine (18.5%). MASM was detected in all rat tissues including the brain, and through the utilization of stable isotope-labeled compounds and standard references, ten metabolites of MASM, namely sophocarpine, oxysophocarpine, and oxymatrine, were tentatively identified. The LD50 of MASM in mice was determined to be 94.25 mg/kg, surpassing that of matrine (83.21 mg/kg) based on acute toxicity results. Histopathological and biochemical analysis indicated no significant alterations in the primary organs of the low- to medium-dosage groups of MASM. These findings provide valuable insights into the efficacy and toxicity profile of MASM.

Diallyl trisulfide inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung cancer via modulating gut microbiota and the PPARγ/NF-κB pathway.

Smoking is the primary risk factor for developing lung cancer. Chemoprevention could be a promising strategy to reduce the incidence and mortality rates of lung cancer. Recently, we reported that A/J mice exposed to tobacco smoke carcinogens displayed the reshaping of gut microbiota. Additionally, garlic oil was found to effectively inhibit the carcinogenic effects of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in lung tumorigenesis. Diallyl trisulfide (DATS), which is the predominant compound in garlic oil, exhibits various biological activities. To further explore the chemopreventive action and potential mechanism of DATS on lung tumorigenesis, we established a lung adenocarcinoma model in A/J mice stimulated by NNK. Subsequently, we employed multi-omics combined molecular biology technologies to clarify the mechanism. The results indicated that DATS significantly decreased the number of lung tumors in NNK induced A/J mice. Interestingly, we discovered that DATS could modulate gut microbiota, particularly increasing the abundance of F. rodentium, which has inhibitory effects on tumor growth. Mechanistically, DATS could activate the PPARγ pathway, leading to the negative regulation of the NF-κB signaling pathway and subsequent suppression of NF-κB-mediated inflammatory factors. Collectively, these findings provide support for DATS as a potential novel chemopreventive agent for tobacco carcinogen-induced lung cancer.

Diallyl Disulfide Blocks Cigarette Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Lung Tumorigenesis via Activation of the Nrf2 Antioxidant System and Suppression of NF-κB Inflammatory Response.

Chemoprevention is a potential strategy to reduce lung cancer incidence and death. Recently, we reported that garlic oil significantly inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis. Diallyl disulfide (DADS) is a bioactive ingredient in garlic. Our goal was to examine the chemopreventive effectiveness and mechanism of DADS on NNK-triggered lung cancer in vivo and in vitro in the current investigation. The results indicated that DADS significantly reduced the number of lung nodules in the NNK-induced A/J mice. Consistent with the in vivo results, DADS markedly inhibited NNK-induced decrease of MRC-5 cells' viability. Mechanistically, DADS could promote Nrf2 dissociated from the Keap1-Nrf2 complex and accelerate Nrf2 nuclear translocation, which in turn upregulates its downstream target genes. Besides, DADS further inhibited the NF-κB signaling cascade, thus reducing the accumulation of inflammatory factors. Collectively, these discoveries supported the potential of DADS as a novel candidate for the chemoprevention of tobacco-carcinogen-induced lung cancer.

A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease.

The Keap1-Nrf2 pathway has been established as a therapeutic target for Alzheimer's disease (AD). Directly inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 has been reported as an effective strategy for treating AD. Our group has validated this in an AD mouse model for the first time using the inhibitor 1,4-diaminonaphthalene NXPZ-2 with high concentrations. In the present study, we reported a new phosphodiester containing diaminonaphthalene compound, POZL, designed to target the PPI interface using a structure-based design strategy to combat oxidative stress in AD pathogenesis. Our crystallographic verification confirms that POZL shows potent Keap1-Nrf2 inhibition. Remarkably, POZL showed its high in vivo anti-AD efficacy at a much lower dosage compared to NXPZ-2 in the transgenic APP/PS1 AD mouse model. POZL treatment in the transgenic mice could effectively ameliorate learning and memory dysfunction by promoting the Nrf2 nuclear translocation. As a result, the oxidative stress and AD biomarker expression such as BACE1 and hyperphosphorylation of Tau were significantly reduced, and the synaptic function was recovered. HE and Nissl staining confirmed that POZL improved brain tissue pathological changes by enhancing neuron quantity and function. Furthermore, it was confirmed that POZL could effectively reverse Aß-caused synaptic damage by activating Nrf2 in primary cultured cortical neurons. Collectively, our findings demonstrated that the phosphodiester diaminonaphthalene Keap1-Nrf2 PPI inhibitor could be regarded as a promising preclinical candidate of AD.

Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and SZM-1209 showed high anti-necroptotic activity (EC50 = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 (Kd,RIPK1 = 85 nM, Kd,RIPK3 > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, SZM-1209 could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, SZM-1209 significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of SZM-1209 against RIPK1, necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.

Receptor-interacting protein kinase 1 (RIPK1) inhibitor: a review of the patent literature (2018-present).

INTRODUCTION: RIPK1 is a critical mediator of inflammation and cell death, which is associated with extensive neurodegenerative and inflammatory diseases. Recently, RIPK1 has aroused the interests of pharmaceutical industry and research institutions. AREAS COVERED: This review focuses on patent literature covering small-molecule inhibitors of RIPK1 since 2018. SciFinder and PubMed databases were used for patent and literature searching. EXPERT OPINION: Studies of RIPK1 inhibitors for the necroptosis pathway have increased dramatically in recent years. To date, dozens of RIPK1 inhibitors have been reported, and several have entered clinical studies. However, the development of RIPK1 inhibitors is still at a preliminary stage. An understanding of the dosage and disease indications of RIPK1 inhibitors, rational structural optimization, and the optimal clinical setting for new structures will require feedback from further clinical trials. Recently, compared with type III inhibitors, the patents on type II inhibitors have dramatically increased. Most of them contain hybrid structures of type II/III inhibitors occupying the ATP-binding pocket and the back hydrophobic pocket of RIPK1. Patents of RIPK1 degraders were also disclosed, but the role of RIPK1 kinase- independent and dependent in promoting cell death and diseases must be considered.

Structure-Based Design of Novel Alkynyl Thio-Benzoxazepinone Receptor-Interacting Protein Kinase-1 Inhibitors: Extending the Chemical Space from the Allosteric to ATP Binding Pockets.

Systemic inflammatory response syndrome (SIRS), characterized by severe systemic inflammation, represents a major cause of health loss, potentially leading to multiple organ failure, shock, and death. Exploring potent RIPK1 inhibitors is an effective therapeutic strategy for SIRS. Recently, we described thio-benzoxazepinones as novel RIPK1 inhibitors and confirmed their anti-inflammatory activity. Herein, we further synthesized novel thio-benzoxazepinones by introducing substitutions on the benzene ring by an alkynyl bridge in order to extend the chemical space from the RIPK1 allosteric to ATP binding pockets. The in vitro cell and kinase assays found that compounds 2 and 29 showed highly potent activity against necroptosis (EC50 = 3.7 and 3.2 nM) and high RIPK1 inhibitory activity (Kd = 9.7 and 70 nM). Prominently, these two analogues possessed better in vivo anti-inflammatory effects than the clinical candidate GSK'772 and effectively blocked hypothermia and deaths in a TNFα-induced SIRS model.

Metallophilic Interaction-Mediated Hierarchical Assembly and Temporal-Controlled Dynamic Chirality Inversion of Metal-Organic Supramolecular Polymers.

The study of dynamic supramolecular chirality inversion (SMCI) not only helps to deepen the understanding of chiral transfer and amplification in both living organizations and artificially chemical self-assembly systems but also is useful for the development of smart chiral nanomaterials. However, it is still challenging to achieve the dynamic SMCI of the self-aggregation of metal-organic supramolecular polymers with great potential in asymmetric synthesis, chiroptical switches, and circular polarized luminescence. Here, we successfully developed a hierarchical coassembly system based on the mPAzPCC and various metal ions with effective chirality transfer and temporal-controlled SMCI. Due to the dynamic self-assembly and hierarchical chirality transfer of the Ag+/mPAzPCC complex driven by metallophilic interaction and coordination, morphological transition with nanoribbons, helical nanoribbons, and chiral nanotubules was successively obtained. Interestingly, the SMCI of chiral nanoaggregates was precisely regulated by solvents and metal ions in the Cu2+/mPAzPCC and Mn2+/mPAzPCC system. Besides, temporal-controlled dynamic SMCI switching from helix to bundled helix was clearly revealed in the aggregation of Cu2+/mPAzPCC, Mn2+/mPAzPCC, and Bi3+/mPAzPCC systems. This work provides a metallophilic interaction-mediated helical assembly pathway to dynamically modulate the chirality of metal-organic complex-based assemblies and deepen the understanding of the hierarchically dynamic self-assembly process, which would be of great potential in metal ion-mediated supramolecular asymmetric catalysis and bioinspired chiral sensing.

Profiling of the chemical space on the phenyl group of substituted benzothiazole RIPK3 inhibitors.

Necroptosis is confirmed as a precisely programmed cell death that is activated in caspase-deficient conditions. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase (MLKL) are the key regulators involved in the signaling pathway. However, accumulating evidence suggests that RIPK1 also works in apoptosis and inflammation pathways independent of necroptosis. Differently, RIPK3 signals necroptosis independent of RIPK1. Thus, identification of specific RIPK3 inhibitors is of great importance for the drug development associated with necroptosis. The benzothiazole carboxamide is a privileged scaffold as RIPK3 inhibitors developed by our group recently. In this study, we work on the phenyl group in-between of benzothiazole and carboxamide to profile the chemical space. Finally, a chlorinated derivative XY-1-127 was found to specifically inhibit necroptosis rather than apoptosis with an EC50 value of 676.8 nM and target RIPK3 with a Kd of 420 nM rather than RIPK1 (Kd = 4300 nM). It was also confirmed to block the formation of necrosome by inhibiting RIPK3 phosphorylation at 1 µM in necroptosis cells. This work discovers the chemical space insights on the phenyl group of the substituted benzothiazole RIPK3 inhibitors and provides a new lead compound for further development.

Roxarsone inhibits hepatic stellate cell activation and ameliorates liver fibrosis by blocking TGF-ß1/Smad signaling pathway.

Hepatic fibrosis is a pathological change caused by chronic liver injury and self-repair, and it is the inevitable stage of the development of chronic liver disease to cirrhosis or even liver cancer. Activation of hepatic stellate cells (HSCs) is a core event in the development of liver fibrosis and blockage of the activation of HSCs has been shown to alleviate liver fibrosis. Roxarsone, an organoarsenic additive, with antibiotic effect, growth promotion and improving feed efficiency, is widely used in livestock and animal production. The purpose of this study was to evaluate the therapeutic effect of Roxarsone on liver fibrosis and explore the possible mechanism. We found that Roxarsone could inhibit transforming growth factor-ß1 (TGF-ß1) induced the activation of HSCs and weaken the migration ability. Moreover, Roxarsone administration significantly ameliorated CCl4-induced liver fibrosis in mice with improvement of liver function and decreases of deposition of extracellular matrix (ECM). Mechanism investigations revealed that Roxarsone specifically inhibited the activation of TGF-ß1/Smad signaling pathway, but had no effect on MAPK and PI3K/AKT pathways. These results suggest that Roxarsone has a protective effect on liver fibrosis which provides a new candidate for the treatment of liver fibrosis.

Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS.

BACKGROUND AND AIMS: Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. APPROACH AND RESULTS: Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine-induced HCC mouse model was screened using a quantitative mass spectrometry-based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL-6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL-6 in HcPCs, causing the acyl protein thioesterase 1-mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL-6 in HcPCs. Clinically, GαS, especially K28-acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. CONCLUSIONS: Malignant progression of HcPCs requires increased K28-acetylated and cytoplasm-translocated GαS, causing enhanced response to IL-6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.

Rational drug design of CB2 receptor ligands: from 2012 to 2021.

Cannabinoid receptors belong to the large family of G-protein-coupled receptors, which can be divided into two receptor types, cannabinoid receptor type-1 (CB1) and cannabinoid receptor type-2 (CB2). Marinol, Cesamet and Sativex are marketed CB1 drugs which are still in use and work well, but the central nervous system side effects caused by activation CB1, which limited the development of CB1 ligands. So far, no selective CB2 ligand has been approved for marketing, but lots of its ligands in the clinical stage and pre-clinical stage have positive effects on the treatment of some disease models and have great potential for development. Most selective CB2 agonists are designed and synthesized based on non-selective CB2 agonists through the classical med-chem strategies, e.g. molecular hybridization, scaffold hopping, bioisosterism, etc. During these processes, the balance between selectivity, activity, and pharmacokinetic properties needs to be achieved. Hence, we summarized some reported ligands on the basis of the optimization strategies in recent 10 years, and the limitations and future directions.

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis.

BACKGROUND: Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study. METHODS: DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation. RESULTS: We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models. CONCLUSIONS: Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.

Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer's Disease.

Receptor-interacting protein kinase 1 (RIPK1) contributes to a broad set of inflammations and necroptosis in human diseases, which also plays an important role in the pathogenesis of Alzheimer's disease (AD). The inhibition of RIPK1 could be a novel strategy to improve cognitive function. SZM679, a highly specific RIPK1 inhibitor (Kd,RIPK1 = 8.6 nM, Kd,RIPK3 > 5000 nM), was developed by our group with superior high antinecroptotic activity (EC50 = 2 nM), and investigated to completely reverse the tumor necrosis factor-induced systemic inflammatory response syndrome. In a streptozocin-induced AD-like mouse model, behavioral tests showed that SZM679 apparently ameliorated learning and memory dysfunction. Nissl staining revealed that SZM679 improved neuronal loss. Moreover, the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex were significantly decreased in the SZM679-treated group. Collectively, SZM679 represents a promising lead structure for the discovery of novel RIPK1 inhibitory anti-AD agents.

Methionine-Derived Organogels as Lubricant Additives Enhance the Continuity of the Oil Film through Dynamic Self-Healing Assembly.

(S)-2-((1-(Hexadecylamino)-4-(methylthio)-1-oxobutan-2-yl)carbamoyl)benzoic acid (HMTA) was efficiently synthesized and successfully applied as an additive to several types of blank lubricant oils. Initially, HMTA self-assembles to fibrous structures and traps blank lubricant oils to form gel lubricants. The prepared gel lubricants show thermo-reversible properties and enhanced lubricating performance by 3∼5-fold. X-ray photoelectron spectrometry of the metal surface and the quartz crystal microbalance illustrated that there are no obvious interactions between HMTA and the metal surface. The results of Fourier transform infrared spectroscopy and X-ray diffraction further confirm that inter/intro-molecular H-bonding interactions are the main driving force for the self-healing of HMTA. Finally, molecular dynamics (MD) simulations show that the number of noncovalent H-bonding interactions fluctuates with time, and this highly dynamic H-bonding network could regulate the self-assembly process and result in the self-healing property of the HMTA organogel, which is consistent with the results of the step-strain tests. Especially, the Hirshfeld independent gradient model method at the quantum level demonstrated that C8/C9 aromatics of 500SN have strong π-π stacking interactions with the aromatic heads of HMTA and van der Waals interactions with the hydrophobic tails of HMTA, which disrupt the self-assembly behavior of the 500SN model. Therefore, the calculation studies offer a rational explanation for the superior lubricant property of the PAO10 gel as compared to that for 500SN.

Targeting Necroptosis as a Promising Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder featured by memory loss and cognitive default. However, there has been no effective therapeutic approach to prevent the development of AD and the available therapies are only to alleviate some symptoms with limited efficacy and severe side effects. Necroptosis is a new kind of cell death, being regarded as a genetically programmed and regulated pattern of necrosis. Increasing evidence reveals that necroptosis is tightly related to the occurrence and development of AD. This review aims to summarize the potential role of necroptosis in AD progression and the therapeutic capacity of targeting necroptosis for AD patients.

Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors.

As a key upstream kinase involved in the activation of necroptosis, receptor-interacting protein kinase 1 (RIPK1) plays a vital role in the treatment of relevant inflammatory diseases. Recently, we described the thio-benzoxazepinones as RIPK1 necroptosis inhibitors. On this basis, we further explored the chemical space of the thio-benzoxazepinones by introducing substitutions on the triazole group and evaluated their anti-necroptotic activity. The structure-activity relationship (SAR) was extended for this series of new derivatives. The best compound 2 with methyl and compound 10 with fluoroethyl were obtained and both specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.5 and 8.9 nM, respectively. They blocked the downstream necroptotic pathway to prevent cell lysis and prevent in vivo inflammation in a dose-dependent manner. This work provides that substituted thio-benzoxazepines can better occupy the hydrophobic cavity and enhance the hydrophobic interaction as promising lead compounds to enhance the in vivo activity of this class of compounds.

Peramivir, an Anti-Influenza Virus Drug, Exhibits Potential Anti-Cytokine Storm Effects.

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF-α by partly intervention of NF-κB activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-α. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS.

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy.

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (5) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3. In this study, using ligand-based substituent-anchoring design strategy, we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3. Among them, a conformational constrained fluorine-substituted derivative (25) exhibited 333-fold selectivity for RIP1 (K d = 15 nmol/L) than RIP3 (K d > 5000 nmol/L). This compound showed highly potent activity against cell necroptosis (EC50 = 8 nmol/L) and systemic inflammatory response syndrome (SIRS) induced by TNF-α in vivo. Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.