ABSTRACT
Dorzagliatin is a new dual action allosteric systemic glucokinase agonist (GKA), which can simultaneously activate the glucokinase (GK) in the pancreas and liver, promote insulin secretion and liver glycogen conversion in patients with type 2 diabetes, and improve pancreatic islets β - Cell function and insulin resistance simultaneously stimulate intestinal GK to regulate the secretion of Glucagon-like peptide-1 to play multiple hypoglycemic effects. As the first marketed GKA drug, it provides a new therapeutic approach for patients with type 2 diabetes. This article reviews the mechanism of action, pharmacokinetics, Drug interaction, clinical research and safety of Dorzagliatin.
ABSTRACT
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Subject(s)
Humans , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/virology , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , High-Throughput Screening Assays/methods , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/therapeutic use , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purificationABSTRACT
The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (Mpro). Here the X-ray crystal structure of Mpro in complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 M) and it is a promising lead compound to develop new antiviral treatment for COVID-19.
ABSTRACT
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 M. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.
ABSTRACT
Objective To investigate the effect of tadpole extract(T871 3) on tumor cells and its mechanism. Methods We studied the effects of T871 3 on proliferation, differentiation and apoptosis of HL 60 cells by cytomorphological observation, cytochemistry and TUNEL method. We also examined gene expression during the induction of apoptosis and differentiation in tadpole extract treated HL 60 cells by in situ hybridization and intact cell mRNA dot blot techniques. Results 1 T871 3 was able to inhibite HL 60 cells proliferation. 2 T871 3 was able to induce HL 60 cells to differentiate along monocyte macrophage lineage at low concentration, and apoptosis at higher concentration. 3 The differentiation of HL 60 cells was accompanied by downregulations of c myc,c myb gene expression, The apoptosis of HL 60 cells was accompanied by downregulations of c\|myc bcl 2 gene expression, suggesting that these genes may be involved in the apoptosis and differentiation process. Conclusion Tadpole extract may have effects on HL 60 cells through changing the oncogene expression. [
