ABSTRACT
Pancreatic cancer is a highly malignant tumor with a poor prognosis. It is very hard to treat pancreatic cancers for their high heterogeneity, complex tumor microenvironment, and drug resistance. Currently, gemcitabine plus nab-paclitaxel, capecitabine and FOLFIRINOX are standard chemotherapy for resectable or advanced metastatic pancreatic cancer. Considering the limited efficacy and toxic side effects of chemotherapy, targeted and immune drugs have gradually attracted attention and made some progress. In this article, we systematically reviewed the chemotherapeutic drugs, targets and related targeted drugs, and immunotherapy drugs for pancreatic cancer.
ABSTRACT
The discovery of drug targets plays a crucial role in drug research. Accurate information of small molecule drug-protein interaction can be provided by label-free target discovery technology without any structural modification at the small molecule. So, the label-free drug target discovery technology had become the powerful tool to discover the targets of drugs. Due to the “multi-component and multi-target” characteristics of traditional Chinese medicines (TCMs), the research on its targets and mechanism had been restricted. Based on potential of the label-free target discovery technology in the research of TCMs, this paper summarized the label-free target discovery technology and its application in TCMs research. It will provide a reference for the discovery of targets of TCMs and a new view for promoting the modernization of TCMs.
ABSTRACT
Tumor brings great threat to human public health. In recent years, incidence rate and mortality of tumor were rapidly increased in the world. Anti-tumor therapies have undergone the development of cytotoxic therapy, targeted therapy, and immunotherapy. Among them, tumor immunotherapy is rapidly developed and becomes an important anti-tumor therapy in recent years, although it also brings some related side effects. Tumor microenvironment (TME) is composed of immune cells, vascular vessels, fibroblasts, the extracellular matrix, etc. TME significantly affects the efficacy of immunotherapy. Macrophages in the TME are named as tumor associated macrophages (TAMs). Recently, increasing studies have shown that TAMs play an important role in the regulation of tumor immunity, especially in tumor immune surveillance and immune escape. Currently, more and more anti-tumor immunotherapy strategies targeting TAMs are at the development stage. Based on the important role of TAMs in the TME and their potential as therapeutic targets in tumor immunotherapy, we first reviewed the subtypes and functions of TAMs, as well as the roles of TAMs in tumors. Furthermore, we summarized the research progress on anti-tumor strategies targeting TAMs and the current status of drug targeting TAMs. The current review will provide new ideas and novel insights for tumor immunotherapy.
ABSTRACT
Hepatitis B virus infection is a serious threat to human life and health. The approved anti-HBV drugs including interferons and nucleos(t)ide analogues have serious adverse effect, rebound phenomena after drug withdrawal, and drug resistance. And the cccDNA cannot be completely eliminated by both of them, which is the reason why a complete cure for hepatitis B cannot be achieved. Therefore, developing anti-HBV drugs directly targeting protein or nucleic acid of HBV remains a current public health priority. Based on the analysis of representative literature from the last decade, this article reviews recent developments in small molecule inhibitors directly targeting HBV from a medicinal chemistry perspective.
ABSTRACT
As one of the major sources of infection, viruses could infect all organisms including bacteria, plants, animals, and humans. Infectious diseases caused by viruses pose a great threat and damage to human health and economic activities all over the world. Adaptor-associated protein kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and a specific key kinase regulating the phosphorylation of AP-2 protein μ2 subunit T156. In the past, AAK1 has been regarded as a feasible biological target for the treatment of nerve pain. Recently, scientists have found that inhibiting AAK1 can regulate endocytosis and inhibit virus invasion into cells. Therefore, AAK1 could be the potential target of anti-virus therapy. This paper reviews the research progress of small molecule AAK1 inhibitors in the field of antiviral, analyzes the future research directions and challenges, and provides new ideas for the development of antiviral drugs targeting AAK1.
ABSTRACT
Cystine/glutamate antiporter [system Xc(-)] is a sodium independent amino acid transporter, which is a heterodimer composed of light chain subunit xCT and heavy chain subunit 4F2hc (CD98) through covalent disulfide bond. System Xc(-) typically mediates cystine uptake and glutamate output, helps to maintain the balance of glutamate, cystine and cysteine inside and outside the cell, regulates the level of glutamate inside and outside the membrane and the synthesis of intracellular glutathione, thus affecting oxidative stress and glutamate neurotoxicity. This review expounds the structure and function of system Xc(-), analyzes the role of the transporter in physiology and pathology, discusses the role and mechanism in different diseases, and discusses the specific research progress of system Xc(-) as a drug target. This review summarizes the research status of system Xc(-) and provides theoretical guidance for further research on system Xc(-) and drug discovery.
ABSTRACT
Nucleocytoplasmic transport is the basic cellular activity of eukaryotic cells, which plays a role in cell physiological and pathological processes. A large amount of evidences indicate that impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to the pathology of neurodegenerative diseases. The regulation of nucleocytoplasmic transport is crucial to elucidate the pathogenesis and intervention in the neurodegenerative diseases. This article summarizes the evidences in disturbed nucleocytoplasmic transport of neurodegenerative diseases in the past two decades, further explores the directions and provides a theoretical basis for the pathogenesis and drug targets in neurodegenerative diseases.
ABSTRACT
Ischemic heart disease (IHD), which has been considered to be exclusively caused by stenosis or occlusion of coronary artery, is a significant cause of morbidity and mortality worldwide. Mitochondrial dysfunction is the main pathological basis of ischemic heart disease and reperfusion injury, and moderate mitochondrial autophagy can selectively remove damage proteins and organelles to maintain intracellular homeostasis, so mitochondrial autophagy is important for maintaining the homeostasis of cardiomyocytes. Natural drugs from plants are widely used in ischemic heart disease. In recent years, more and more natural drugs have been proven to alleviate myocardial cell damage after ischemia/reperfusion through mitochondrial autophagy. This paper reviews the research progress of natural drugs from plants medicines regulating mitochondrial autophagy in the treatment of ischemia heart disease.
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Macrophages are highly plastic and heterogeneous. In different types of inflammatory diseases, or at different stages of the same disease, macrophages can undergo phenotypic transformation to elicit different functions. Hence, exploring new regulatory mechanism of macrophage polarization and seeking for new key mediators will lay the foundation for the diagnosis and treatment of macrophage-related diseases, such as inflammatory diseases, autoimmune diseases, and cancer. Interferon regulatory factors (IRFs) have been reported to play an important role in the maturation and differentiation of macrophages. In this review, we will describe the structure and modulation pattern of IRFs, and then further summarize the molecular mechanism and signal regulation network of IRFs in pathological processes of related diseases through controlling macrophage polarization. Our review will explore the new therapeutic strategy and potential drug targets for related diseases.
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Xiaoshuan Tongluo formula is effective in treating mental retardation and speech astringency caused by cerebral thrombosis, but its mechanism remains unclear. In this investigation, by collecting the chemical constituents from Xiaoshuan Tongluo formula and the targets related to stroke, we obtained 1 251 constituents from the formula and 10 drug targets related with stroke. We established 18 prediction models of compound-target interaction for 10 stroke-related targets, using molecular docking method and machine learning methods includes Naive Bayesian and recursive partitioning based on the input of molecular fingerprints and molecular descriptors. Using these models, we predicted the active chemical constituents from Xiaoshuan Tongluo formula and their drug targets, 153 potential active constituents were discovered, 22 among them could interact with at least two drug targets related with stroke. On this basis, the chemical constituent-target network was constructed using network construction software, and then the important metabolic pathways of the targets were identified by using Gene-Ontology (GO) enrichment analysis, such as blood coagulation, positive regulation of angiogenesis, positive regulation of ion transport and so on. On this basis, a target-pathway network was constructed. In conclusion, using machine learning, molecular docking, virtual screening, data mining and network construction, this study explored and partially revealed the active chemical constituents and chemical constituent-target-pathway network action mechanism of Xiaoshuan Tongluo formula against stroke, which will provide important information for its further study.
ABSTRACT
italic>N-Acetylaspartate (NAA) is a highly abundant brain metabolite. Nowadays, as an important marker reflecting the function of nervous system, NAA is widely used in the results analysis of nuclear magnetic resonance spectroscopy (1H MRS). NAA is synthesized in mitochondria of neurons and metabolized in oligodendrocytes. Additionally, NAA may be converted to the dipeptide N-acetylaspartylglutamate (NAAG), and catabolized into NAA and glutamate in astrocytes. NAA is related to a variety of central nervous system diseases, including Canavan disease, multiple sclerosis, depression, schizophrenia and other mental diseases. Therefore, NAA may be a biomarker of these diseases, and its related enzymes may be used as therapeutic targets for drug screening. Here, we combined the current research on the molecular mechanisms of NAA to reveal the process of NAA generation, metabolism and transport in the brain, explain the possible physiological effects of NAA and discuss its relationship with central nervous system diseases, explore the prospect of NAA in disease prediction and diagnosis, as well as the targeted treatment that may become the breakthrough of refractory diseases.
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West Nile virus is a flavivirus transmitted by culex mosquitoes. People are generally susceptible to it, West Nile virus infection can cause west Nile fever, which can develop West Nile viral encephalitis and even lead to death. There are currently no approved specific antiviral drugs against West Nile virus. Therefore, seeking effective West Nile virus inhibitors is a hot topic in current community of medicinal chemistry. In this article, based on the main targets of West Nile virus, we summarize the new progress research on West Nile virus inhibitors.
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Adenovirus is a common cause of infection in children and adults with acute respiratory tract, gastrointestinal tract and urinary tract. It can cause serious and even fatal infections in patients with low immune function. Therefore, it poses a great threat to human health. Currently, there are no specific anti-adenoviral drugs in market. With in-depth investigation of the pathogenic mechanism and biological characteristics of adenovirus, and the rapid development of drug screening technology, new generation of anti-adenovirus drug targets and related inhibitors have been discovered, providing new options for treatment. This review selects the representative case studies in recent years and summarizes the advances in anti-adenoviral medicinal chemistry.
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Viral infections have always threatened human health. Broad-spectrum antiviral agents (BSAs) can either target host proteins that are essential for viral replication, or act on multiple viruses or multiple genotypes of the same virus. More importantly, BSAs could reduce the possibility of drug resistance. From the perspective of medicinal chemistry, this review summarizes recent advances in the research of broad-spectrum antiviral drugs with privileged structures or targeting specific targets in the viral life cycle.
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Hepatitis C virus (HCV) infection is one of the global public health issues. Approximately, 130-150 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. From the point of view of medicinal chemistry, we summarize and discuss current endeavors towards the discovery and development of novel inhibitors with various scaffolds or distinct mechanisms of action.
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Norovirus (NoV) is the main pathogen causing the global acute gastroenteritis in humans and NoV infection has become an important public health problem that threatens human health. Because of the lack of appropriate animal models and in vitro cell culture models, the development of NoV biology and antiviral research has been restricted, and there is currently no effective antiviral drug or vaccine against NoV. In the past few years, considerable progress has been made toward the development of norovirus antivirals. This review selects the most representative research examples and provides an overview of recent advances in anti-norovirus drugs and vaccines.
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The outbreak of the influenza viruses (IFV) caused significant harm to our health and life. Human infections caused by pathogenic avian influenza virus (AIV) have continually brought great panic and death threats to people all over the world. With the in-depth study of the biological characteristics of influenza viruses and the rapid development of drug discovery screening technology, a new generation of anti-influenza drug targets and their inhibitors have been continuously discovered, providing more options for the treatment of influenza. From the point of view of medicinal chemistry, this review summarizes and discusses current endeavours towards the discovery and development of novel inhibitors and also provides examples illustrating new methodologies that contribute to the identification of novel anti-influenza drugs.
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Respiratory syncytial virus (RSV) is the main pathogen causing respiratory infections in infants, the elderly, and immunocompromised individuals. Currently, ribavirin and the humanized monoclonal antibody palivizumab are commonly used for lower respiratory tract infections caused by RSV. However, their clinical application has been limited by their efficacy, economy and safety. Therefore, it is necessary to develop new RSV inhibitors to meet the needs of clinical prevention and treatment. This paper selects typical research cases and reviews the research progress of different target inhibitors from the perspective of medicinal chemistry.
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At present, the anti-HCMV (human cytomegalovirus) drugs have some problems, such as moderate activity, poor bioavailability, which urge people to develop new anti-HCMV drugs. With the continuous study on the pathogenesis and biological characteristics of HCMV and the rapid development of new drug design strategies, new generation of anti-HCMV targets and drugs have been identified. This review selects the most representative research examples in recent years, and summarizes the new targets and research progress of anti-HCMV drugs from the perspective of medicinal chemistry.
ABSTRACT
At present, the most widely used anti-herpesviruses drugs are acyclovir (ACV) and its derivatives, but the emergence of herpesvirus resistance to these drugs forces people to continue to seek new anti-herpesviruses drugs. More and more new targets and inhibitors against herpesviruses have been discovered, one reason is the in-depth study of the biological characteristics and pathogenic mechanism of herpesviruses, and the other is the rapid development of new drug design and screening technology. Therefore, there are more options for the treatment of herpes infections. This review summarizes the representative achievements in the field of anti-herpesviruses drugs in recent years.