Latest ArticlesThe technology of lipid-drug conjugates is developed on the basis of prodrug principle, which overcomes some drawbacks of drugs via increasing the lipophilicity of hydrophilic or poorly soluble drugs to promote the absorption of drugs and enhance the curative effect. This article sums up the research progress of lipid-drug conjugates from the chemical synthesis methods of conjugates, the types of conjugates, the influence on biological activity of drugs, the application in nanoparticles for drug delivery and the mechanism of absorption and degradation.
Tumor immune therapy has been remarkably successful in recent years and several kinds of PD-1/PD-L1 (programmed death-1/programmed death-ligand 1) antibody drugs have been approved by the FDA for treatment of advanced malignant neoplasms. However, as biomacromolecules these antibody drugs have certain drawbacks such as high cost, injection-only administration and immunogenicity; thus, we turned to small molecules that have lower immune risks and better modifiability. Considering the structural diversity of natural products, we chose to investigate the active components in Panax ginseng, a famous and highly valued traditional Chinese medicine. Nine compounds were separated and identified in this research using a HPLC-coupled MS system, and 3 PD-1 binding compounds were identified using the SPR method. The PD-1/PD-L1 inhibitory ability of ginsenoside Rg1, as a representative ginsenoside, was verified by cytopharmacological methods. This research provides a new method for the identification of immune blockade inhibitors in natural products.
Drug-drug complexes play important roles in improving the physicochemical properties of drugs including the solubility, dissolution rate and stability of the active pharmaceutical ingredients (APIs). In this paper, the design, synthesis, characterization, changes in physicochemical and pharmacologic properties, structural polymorphisms and the research and development pipelines of a variety of drug-drug cocrystals/salts synthesized based on the crystal engineering design are reviewed. This may provide theoretical support for the development of the new solid-state combinational drugs.
Epithelial cell adhesion molecule (EpCAM) is a popular target for cancer therapy. In this research, 3 nanobodies with high specificity and endocytosis activity against EpCAM were developed, which provides a basis for the study of immunotoxin based on EpCAM. In our preliminary experiments, we have immunized a camel with EpCAM-Fc antigen and constructed a high-quality phage display library. Seventeen nanobodies with different complementarity determining region (CDR) 3 sequences have been screened after 3 rounds of biopanning by phage display technology. The animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Fudan University School of Pharmacy. After purification, 7 nanobodies showed high cell binding activity by fluorescent activated cell sorting (FACS) identification. Furthermore, 3 nanobodies presented high endocytosis activity based on FACS and laser confocal microscopy, which also showed high affinity to EpCAM measured by ForteBio. According to this study, we aimed to provide a novel alternative approach to the EpCAM-targeted therapy and to provide guidance for the study of nanobody based immunotoxins for other targets.
The 2-oxoglutarate-dependent dioxygenase (2-ODD) gene is regarded as the key enzyme gene involved with aryl naphthalene lignan-podophyllotoxin synthesis. To study the expression pattern and function of the Sc2-ODD gene, a full-length cDNA of the gene was cloned. Bioinformatic analysis, the expression pattern, and prokaryotic expression and purification were implemented. The open reading frame of Sc2-ODD gene was 1 077 bp and encoded 358 amino acids with a molecular weight of 40.16 kD. The Sc2-ODD protein contained the conserved 2OG-FeII-oxy sequence of the 2-ODD protein. The results of phylogenetic analysis revealed that Sc2-ODD is most closely related to Corchorus olitorius 2-ODD. qRT-PCR results showed that Sc2-ODD expression displayed obvious up-regulation at the fruit-swelling stage, then down-regulation in the fruit-coloring period. The Sc2-ODD gene was cloned into the bacterial expression vector pGS21T, the recombinant Sc2-ODD protein was expressed in Escherichia coli Rosetta (DE3) cells and the fusion protein was obtained and purified by GST fusion protein purification technology. This study will lay a foundation for further research on the function and expressional regulation of the Sc2-ODD gene in the aryl naphthalene lignans biosynthesis pathway, and also provides a scientific basis for improving the lignan content and the medicinal quality of Schisandra chinensis using plant genetic engineering.
Eighteen dihydroartemisinin-fluoroquinolone molecules conjugated with L-homoserine were designed and synthesized using fragmented drug splicing approaches. The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis (MTB) and the lipid-lowering target PCSK9 were evaluated. The bioassay test results showed that most of the synthesized molecules had anti-tuberculosis (anti-TB) activity. Five compounds showed greater than 80% inhibitory activity against MTB in the replication state and three compounds exhibited more than 50% inhibitory activity against H37Rv in the non-replication state. A structure-activity relationship analysis demonstrated that TM2 series compounds (Boc protection) have better anti-TB activity than TM1 series compounds (Cbz protection). There were 13 compounds with strong inhibitory activity toward PCSK9 (>73%) and TM1-3 compounds reached 92%. The determination of physical parameters showed that all the molecules are largely nontoxic. The structure-toxicity relationship analysis showed that the safety of TM2 is higher than that of TM1 in all parameters, perhaps related to the protecting group of the amino acid in the target molecule, and provides new ideas for the design and structural modification of subsequent molecules. This study sets a precedent for L-homoserine as a linking structural unit in multi-target drug molecules.
Chalcone synthase (CHS) is the rate-limiting enzyme involved in the biosynthetic pathway of flavonoids in Glycyrrhiza uralensis. It plays an important role in the regulation and control of flavonoids biosynthesis. In this study, X-ray irradiated G. uralensis samples with high or low content of flavonoids were studied. The CHS gene polymorphism in these samples were analyzed, the specific haplotypes were identified, and CHS function was parsed. 109 CHS cDNA sequences with a length of 1 170 bp were cloned, 220 variable sites (116 missense mutation sites) were found and 85 haplotypes were identified, which encoded 65 amino acid sequences with 96 variable sites. aa-20 and aa-45 were the most common amino acid sequences in samples with high flavonoid content, while aa-11 was the most sequence in samples with low flavonoid content. Molecular docking results showed that the mutation sites at 383 in aa-20 and 229 in aa-45 were related to substrate binding, while the mutation sites at 383 and 229 in aa-11 were not involved. Therefore, we speculate that the two mutation sites have significant influence on the function of CHS. We analyzed a large number of CHS cDNA sequences and identified the important functional sites, which will provide a basis for further functional studies. This paper will provide ideas for further research of the molecular regulation of the flavonoid biosynthetic pathway in G. uralensis.
Ferroptosis is a cell death path for the abnormal accumulation of iron dependent reactive oxygen species, which leads to the dysregulation of redox homeostasis. As a new type of cancer treatments, ferroptosis has attracted extensive attention of researchers. With the development of nanoscience, various functional nanomaterials can produce H2O2, exhaust glutathione, and gather Fenton reaction catalysts in tumor site. Therefore, these nanomaterials can play a stronger role in tumor inhibition in coordination with the ferroptosis-inducing agents. Firstly, this paper introduced the mechanism of ferroptosis and the feasibility of ferroptosis-inducing strategy in cancer therapy. Secondly, we summarized the construction strategies of the ferroptosis-inducing nanomedicines for cancer therapy, including accelerating intracellular Fenton reaction, inhibiting the activity of glutathione peroxidase 4, and increasing the exogenous delivery of lipid peroxides. In addition, we also discussed the combination therapy based on ferroptosis, including the combination of ferroptosis with traditional therapy strategies (combined with apoptosis-inducing drugs, immunotherapy and gene therapy) and external energy (including ultrasound therapy and photodynamic therapy). Finally, the expectations and challenges of ferroptosis-inducing nanomedicines for cancer therapy in the future were discussed.
The pharmacodynamic material basis and mechanisms of Ju-Hong Tan-Ke liquid (JHTKL) for its anti-tussive, anti-asthmatic and expectorant effects were investigated by using network pharmacology. We collected, screened, and predicted potential targets and signaling pathways for 24 compounds in the 8 herbs of JHTKL and grouped them according to their efficacy. Combined with the evidence analysis in the literature database, we explored molecular mechanisms of the components of this formula in different diseases and analyzed their compatibility laws. To verify the network analysis results, we used software to perform molecular docking of a part of the pivotal targets with their corresponding compounds. The results show that the main active ingredients in JHTKL may be naringin, L-ephedrine, glaucogenin C, amygdalin, deoxyschizandrin, neotuberostemonine, pachymic acid and glycyrrhizic acid. Moreover, efficacy groups of JHTKL may play a role by acting on pivotal gene targets such as the muscarinic acetylcholine receptor M1, acetylcholinesterase, beta-2 adrenergic receptor, prostaglandin G/H synthase 2, tumor necrosis factor, epidermal growth factor receptor and biological pathways such as the neuroactive ligand-receptor interaction, cholinergic synapses, calcium signaling pathway, NF-kappa B signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. In this study, we have confirmed the pharmacodynamic material basis and mechanisms of JHTKL by using network pharmacology, laying a foundation for improving the quality standards of JHTKL and providing a reference basis for its potential expansion in clinical applications.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this paper, we report the validation and use of bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening for SARS-CoV-2 virus 3CL protease inhibitors. The results show that the method is able to monitor the cleavage efficiency of 3CL protease with good reproducibility (Z' factor is 0.59), and is consistent with antiviral activity analysis in cell culture. This work demonstrates that this method can be applied to the screening and evaluation of 3CL protease inhibitors, providing a powerful tool for the development of new drugs.
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