Tubulointerstitial nephritis antigen-like 1 promotes the progression of liver fibrosis after HCV eradication with direct-acting antivirals.

Although therapies based on direct-acting antivirals (DAAs) effectively eradicate hepatitis C virus (HCV) in patients, there is still a high risk of liver fibrosis even after a sustained virological response. Therefore, it is of great clinical importance to understand the mechanism of potential factors that promote liver fibrosis after virological cure by treatment with DAAs. Here, we found that tubulointerstitial nephritis antigen-like 1 (TINAGL1) is significantly increased in HCV-infected hepatocytes and in the liver of patients with liver fibrosis, and that higher TINAGL1 expression persists in HCV-eradicated hepatocytes after treatment with DAAs.

Lycorine esters exert anti-HCoV-OC43 effect through reversibly acylating cysteine residue in the nsp 12 NiRAN domain.

By introducing ester warheads into the hydroxyl groups in lycorine (1), three types of lycorine mono-ester or di-ester analogues were synthesized and evaluated for their antiviral activities against HCoV-OC43. Most of them showed higher selective indexes (SI) than 1, up to nearly 14 times. Using compound 6b as a probe, we firstly demonstrated that lycorine esters directly targeted nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain in the non-structural protein 12 (nsp 12) by reversibly acylating Cys12 to induce the shrink of NiRAN pocket and block the viral replication, different from the known RdRp inhibitors.

Three-dimensional intelligent monitoring and early warning technology for tailings ponds based on spatiotemporal fusion of multisource big data.

To solve the difficult problems of tailings dam instability and environmental pollution, multisource information perception, prediction and early warning technology for tailings dams are investigated. Taking a tailings pond in China as an example, a three-dimensional visualization intelligent management platform based on the spatiotemporal fusion of multisource big data is established to realize intelligent real-time monitoring, prediction and early warning of tailings dams. A monitoring system for air-space-ground integration was developed via high-resolution optical image recording, unmanned aerial vehicles (UAVs), radar, video surveillance and displacement sensors.

Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed -1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element.

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.

Synthesis, Structure and Properties of Polyester Polyureas via a Non-Isocyanate Route with Good Combined Properties.

Polyureas have been widely applied in many fields, such as coatings, fibers, foams and dielectric materials. Traditionally, polyureas are prepared from isocyanates, which are highly toxic and harmful to humans and the environment. Synthesis of polyureas via non-isocyanate routes is green, environmentally friendly and sustainable.

Discovery and development of novel 10,12-disubstituted aloperine derivatives against HCoV-OC43 by targeting allosteric site of host TMPRSS2.

By inducing steric activation of the 10CH bond with a 12-acyl group to form a key imine oxime intermediate, 20 novel (10S)-10,12-disubstituted aloperine derivatives were successfully synthesized and assessed for their antiviral efficacy against HCoV-OC43. Of them, compound 3i exhibited the moderate activities against HCoV-OC43, as well as against the SARS-CoV-2 variant EG.5.

Erratum: Author correction to 'Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects' [Acta Pharmaceutica Sinica B 13 (2023) 2138-2151].

[This corrects the article DOI: 10.1016/j.apsb.

Design, synthesis and biological evaluation of biaryl amide derivatives against SARS-CoV-2 with dual-target mechanism.

The COVID-19 pandemic highlights the urgent need to develop effective small-molecule antivirals. Thirty-three novel biaryl amide derivatives were synthesized and evaluated for anti-coronaviral activity. Some significant SARs were uncovered and the intensive structure modifications led to the most active compounds 8b and 8h.

Design, synthesis and triglyceride-lowering activity of tricyclic matrine derivatives for the intervention of non-alcoholic fatty liver disease.

Thirty new tricyclicmatrinic derivatives were successively synthesized and evaluated for their inhibitory activity on the accumulation of triglycerides (TG) in AML12 cells, using 12 N-m-trifluoromethylbenzenesulfonyl matrine (1) as the hit compound. Among the analogues, compound 7n possessing 11-trimethylbutylamine quaternary exerted the highest in vitro TG-lowering potency, as well as a good safety profile. 7n significantly attenuated the hepatic injury and steatosis, and ameliorated dyslipidemia and dysglycemia in the mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet.

Synthesis of peptidomimetics as antibiotic adjuvants for combination with aztreonam to combat MDR Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the multipledrug-resistant (MDR) Gram-negative pathogens with few drugs available for treatment. Antibiotic adjuvant approach provides an alternative and complementary strategy. In this study, the stereo-structure-activity relationship of monobactams against MDR Gram-negative organisms was extended.

USP2 promotes tumor immune evasion via deubiquitination and stabilization of PD-L1.

The abnormal upregulation of programmed death ligand-1 (PD-L1) on tumor cells impedes T-cell mediated cytotoxicity through PD-1 engagement, and further exploring the mechanisms regulation of PD-L1 in cancers may enhance the clinical efficacy of PD-L1 blockade. Here, using single-guide RNAs (sgRNAs) screening system, we identify ubiquitin-specific processing protease 2 (USP2) as a novel regulator of PD-L1 stabilization for tumor immune evasion. USP2 directly interacts with and increases PD-L1 abundance in colorectal and prostate cancer cells.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs.

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound (IMBZ18G) is highly effective and against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with -lactamase inhibitor avibactam, and the MIC values against MDR were reduced up to 4-512 folds X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of results from the dual inhibition of the common PBP3 and some class A and C -lactamases.

Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1).

A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis.

Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR).

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via collagen type I α 1 (COL1A1)-promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9-p-isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC value of 8.19 μmol/L and SI value of 8.

Discovery of new riminophenazine analogues as antimycobacterial agents against drug-resistant Mycobacterium tuberculosis.

Twenty-three new riminophenazine and pyrido[3,2-b]quinoxaline derivatives were prepared and examined for their antimycobacterial activities against Mycobacterium marinum and Mycobacterium tuberculosis H37Rv, taking clofazimine (1) as the lead. Structure-activity relationship (SAR) analysis revealed that the introduction of a heterocycle or diethylamine substituted benzene moiety on the N-5 atom might be beneficial for activity. The most potent compound 7m also displayed enhanced activity against wild-type as well as multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB clinical isolates, with the MICs ranging from 0.

A Non-Isocyanate Route to Poly(Ether Urethane): Synthesis and Effect of Chemical Structures of Hard Segment.

A series of non-isocyanate poly(ether urethane) (PEU) were prepared by an environmentally friendly route based on dimethyl carbonate, diols and a polyether. The effect of the chemical structure of polyurethane hard segments on the properties of this kind of PEU was systematically investigated in this work. Polyurethane hard segments with different structures were first prepared from hexamethylene di-carbamate (BHC) and different diols (butanediol, hexanediol, octanediol and decanediol).

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation.

Sixty palmatine (PMT) derivatives were synthesized and evaluated for antiplatelet aggregation taking berberine as the lead, and the structure-activity relationship was first systematically described. Among them, compound showed the best potency in reducing adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent manner. It greatly suppressed ADP-induced platelet aggregation, activation, and Akt phosphorylation in vitro and ex vivo after oral administration to mice.

Clofazimine derivatives as potent broad-spectrum antiviral agents with dual-target mechanism.

Thirty-two clofazimine derivatives, of which twenty-two were new, were synthesized and evaluated for their antiviral effects against both rabies virus and pseudo-typed SARS-CoV-2, taking clofazimine (1) as the lead. Among them, compound 15f bearing 4-methoxy-2-pyridyl at the N5-position showed superior or comparable antiviral activities to lead 1, with the EC values of 1.45 μM and 14.

Structure-activity relationship and biological evaluation of 12 N-substituted aloperine derivatives as PD-L1 down-regulatory agents through proteasome pathway.

Twenty-nine 12 N-substituted aloperine derivatives were synthesized and screened for suppression on PD-L1 expression in H460 cells, as a continuation of our work. Systematic structural modifications led to the identification of compound 6b as the most active PD-L1 modulator. Compound 6b could significantly down-regulate both constitutive and inductive PD-L1 expression in NSCLC cells, and successively enhance the cytotoxicity of co-cultured T cells against tumor cells at the concentration of 20 μM.

Discovery and evolution of 12N-substituted aloperine derivatives as anti-SARS-CoV-2 agents through targeting late entry stage.

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile.

Structure-activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure-activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity.

Clofazimine: A Promising Inhibitor of Rabies Virus.

With an almost 100% mortality rate, rabies virus (RABV) infection is a global concern. Limited post-exposure prophylaxis and lack of an effective treatment necessitate novel antiviral therapies against RABV. Here, using a high-throughput screening (HTS) method developed in our lab, 11 candidates with anti-RABV activity were identified from a library of 767 clinical drugs.