scholarly journals Multiscale Characterization Reveals Oligomerization Dependent Phase Separation of Primer-independent RNA Polymerase nsp8 From SARS-CoV-2

2021 ◽  
Author(s):  
Jinxin Xu ◽  
Xin Jiang ◽  
Yan Dong ◽  
Changli Ma ◽  
Hanqiu Jiang ◽  
...  
Keyword(s):  
Phase Separation ◽  
Stability Analysis ◽  
Drug Target ◽  
Rna Replication ◽  
Therapeutic Agents ◽  
Synthesis Mechanism ◽  
Thermo Stability ◽  
Insight Into ◽  
Important Drug ◽  
Novel Therapeutic

Abstract RNA replication and transcription machinery is an important drug target for fighting against coronavirus. Non-structure protein nsp8 was proposed harboring primase activity. However, the RNA primer synthesis mechanism of nsp8 is still largely unknown. Here, we purified dimer and tetramer forms of SARS-CoV-2 nsp8. Combined with DLS, SANS and thermo-stability analysis, we found that both dimer and tetramer become loosened and destabilized with decreasing salt concentration, and the dimer form is more stable than the tetramer form. Further investigation showed that nsp8 dimer and tetramer can undergo phase separation but exhibit different phase separation behaviors. nsp8 dimer can form liquid-like droplets in the buffer with a low concentration of NaCl; phase separation of nsp8 tetramer depends on the assistance of RNA. Our findings on different phase separation behaviors of nsp8 dimer and tetramer could provide novel insight into the primer synthesis mechanism in coronavirus and facilitate developing novel therapeutic agents against SARS-CoV-2.

Platypus venom genes expressed in non-venom tissues

2009 ◽  
Vol 57 (4) ◽  
pp. 199 ◽  
Author(s):  
Camilla M. Whittington ◽  
Katherine Belov
Keyword(s):  
Tissue Expression ◽  
Therapeutic Agents ◽  
New Era ◽  
Functional Studies ◽  
Ornithorhynchus Anatinus ◽  
Pharmacological Studies ◽  
Platypus Genome ◽  
Insight Into ◽  
Novel Therapeutic ◽  
The Way

The venom of the platypus (Ornithorhynchus anatinus) has been poorly studied to date. The recent publication of the platypus genome heralds a new era for mammalian venom research and is a useful starting tool for functional studies of venom components. We report here the patterns of tissue expression of two venom genes, OvNGF and OvCNP, in order to provide some insight into the functions of the proteins they produce and to pave the way for further functional and pharmacological studies, which may lead to the development of novel therapeutic agents.

scholarly journals Exosomes in Severe Asthma: Update in Their Roles and Potential in Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Esmaeil Mortaz ◽  
Shamila D. Alipoor ◽  
Mohammad Varahram ◽  
Hamidreza Jamaati ◽  
Johan Garssen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Communication ◽  
Cell Types ◽  
Therapeutic Agents ◽  
Lipid Mediators ◽  
Inflammatory Microenvironment ◽  
Intracellular Communication ◽  
Underlying Mechanisms ◽  
Insight Into ◽  
Novel Therapeutic

Exosomes are nanosized vesicles and have recently been recognized as important players in cell-to-cell communication. Exosomes contain different mediators such as proteins, nucleic acids (DNA, mRNA, miRNAs, and other ncRNAs), and lipid mediators and can shuttle their exosomal content to both neighboring and distal cells. Exosomes are very effective in orchestrating immune responses in the airways and all cell types can contribute to the systemic exosome pool. Intracellular communication between the broad range of cell types within the lung is crucial in disease emphasizing the importance of exosomes. In asthma, exosomes affect the inflammatory microenvironment which ultimately determines the development or alleviation of the pathological symptoms. Recent studies in this area have provided insight into the underlying mechanisms of disease and led to interest in using exosomes as potential novel therapeutic agents.

scholarly journals Discovery of Novel Inhibitors Targeting HDM2: Virtual Screening, Molecular Dynamics Simulation and Binding affinity predication

2021 ◽  
Author(s):  
Feng Cao ◽  
Liang Chen ◽  
Feng Xiong ◽  
Xingyong Liu ◽  
Li Zhang
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Drug Target ◽  
Dynamics Simulation ◽  
Free Energies ◽  
Tumor Treatment ◽  
Mechanism Of Interaction ◽  
Insight Into ◽  
Important Drug ◽  
Binding Free Energies

Abstract HDM2(human double-minute 2 protein) is an important drug target for tumor treatment. The main physiological function of HDM2 is to negatively regulate the tumor suppressor protein p53 and inhibit the normal biological function of p53, which leads to the occurrence and development of tumors. Therefore, the discovery of small molecules that can inhibit the activity of HDM2 is a promising cancer therapy. In this study, we reported a virtual screening as an effective strategy to discover potential HDM2 inhibitors from the Specs database. Then 100 ns all-atom molecular dynamics (MD) simulation and binding free energies calculated were carried out on the selected compounds. In conclusion, we reported seven prospective candidates with novel skeletons among them Hit4 is a potential HDM2 inhibitor and provided an insight into the mechanism of interaction of the compounds to HDM2 target.

Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

2019 ◽  
Vol 25 (25) ◽  
pp. 2772-2787 ◽  
Author(s):  
Raghu P. Mailavaram ◽  
Omar H.A. Al-Attraqchi ◽  
Supratik Kar ◽  
Shinjita Ghosh
Keyword(s):  
Drug Target ◽  
Therapeutic Agents ◽  
G Protein Coupled Receptors ◽  
Current Status ◽  
Renal Diseases ◽  
Adenosine A3 Receptor ◽  
Drug Candidates ◽  
Novel Drugs ◽  
The Family ◽  
G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

scholarly journals Chalepin and Chalepensin: Occurrence, Biosynthesis and Therapeutic Potential

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1609
Author(s):  
Lutfun Nahar ◽  
Shaymaa Al-Majmaie ◽  
Afaf Al-Groshi ◽  
Azhar Rasul ◽  
Satyajit D. Sarker
Keyword(s):  
Medicinal Plant ◽  
Critical Appraisal ◽  
Therapeutic Potential ◽  
Therapeutic Agents ◽  
Review Article ◽  
Natural Distribution ◽  
Antiplatelet Aggregation ◽  
Ruta Chalepensis ◽  
The Family ◽  
Novel Therapeutic

Dihydrofuranocoumarin, chalepin (1) and furanocoumarin, chalepensin (2) are 3-prenylated bioactive coumarins, first isolated from the well-known medicinal plant Ruta chalepensis L. (Fam: Rutaceae) but also distributed in various species of the genera Boenminghausenia, Clausena and Ruta. The distribution of these compounds appears to be restricted to the plants of the family Rutaceae. To date, there have been a considerable number of bioactivity studies performed on coumarins 1 and 2, which include their anticancer, antidiabetic, antifertility, antimicrobial, antiplatelet aggregation, antiprotozoal, antiviral and calcium antagonistic properties. This review article presents a critical appraisal of publications on bioactivity of these 3-prenylated coumarins in the light of their feasibility as novel therapeutic agents and investigate their natural distribution in the plant kingdom, as well as a plausible biosynthetic route.

scholarly journals Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1781
Author(s):  
Gustavo A. Arias-Pinilla ◽  
Helmout Modjtahedi
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibodies ◽  
Antibody Therapy ◽  
Therapeutic Targets ◽  
Poor Response ◽  
Therapeutic Agents ◽  
Therapeutic Interventions ◽  
Western World ◽  
Wide Range ◽  
Novel Therapeutic

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.

scholarly journals Artificial intelligence-based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shingo Tsuji ◽  
Takeshi Hase ◽  
Ayako Yachie-Kinoshita ◽  
Taiko Nishino ◽  
Samik Ghosh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Deep Learning ◽  
Drug Target ◽  
Target Genes ◽  
Drug Repositioning ◽  
Therapeutic Targets ◽  
Machine Learning Techniques ◽  
Computational Framework ◽  
Novel Therapeutic

Abstract Background Identifying novel therapeutic targets is crucial for the successful development of drugs. However, the cost to experimentally identify therapeutic targets is huge and only approximately 400 genes are targets for FDA-approved drugs. As a result, it is inevitable to develop powerful computational tools that can identify potential novel therapeutic targets. Fortunately, the human protein-protein interaction network (PIN) could be a useful resource to achieve this objective. Methods In this study, we developed a deep learning-based computational framework that extracts low-dimensional representations of high-dimensional PIN data. Our computational framework uses latent features and state-of-the-art machine learning techniques to infer potential drug target genes. Results We applied our computational framework to prioritize novel putative target genes for Alzheimer’s disease and successfully identified key genes that may serve as novel therapeutic targets (e.g., DLG4, EGFR, RAC1, SYK, PTK2B, SOCS1). Furthermore, based on these putative targets, we could infer repositionable candidate-compounds for the disease (e.g., tamoxifen, bosutinib, and dasatinib). Conclusions Our deep learning-based computational framework could be a powerful tool to efficiently prioritize new therapeutic targets and enhance the drug repositioning strategy.

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