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novel drugs

Yi-Lei Fan, Xiao-Hong Jin, Zhong-Ping Huang, Hai-Feng Yu, Zhi-Gang Zeng, Tao Gao, Lian-Shun Feng
Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity...
March 7, 2018: European Journal of Medicinal Chemistry
Alejandro Amor-Coarasa, James Kelly, Shashikanth Ponnala, Yogindra Vedvyas, Anastasia Nikolopoulou, Clarence Williams, Moonsoo M Jin, J David Warren, John W Babich
INTRODUCTION: CXCR4 specific [18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [18 F]RPS-544 with the previously published [18 F]-3 ([18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression...
January 31, 2018: Nuclear Medicine and Biology
Vesa M Olkkonen, Juha Sinisalo, Matti Jauhiainen
Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk...
March 8, 2018: Atherosclerosis
Urmi Bajpai, Abhishek Kumar Mehta, Kandasamy Eniyan, Avni Sinha, Ankita Ray, Simran Virdi, Shazeb Ahmad, Aridni Shah, Deepanksha Arora, Devyani Marwaha, Gunjan Chauhan, Prarthna Saraswat, Punita Bathla, Ruchi Singh
Bacteriophages are being considered as a promising natural resource for the development of alternative strategies against mycobacterial diseases, especially in the context of the wide spread occurrence of drug-resistance amongst the clinical isolates of M. tuberculosis. However, there isn't much information documented on mycobacteriophages from India. Here, we report the isolation of 17 mycobacteriophages using M. smegmatis as the bacterial host where 9 phages also lyse M. tuberculosis H37Rv. We present detailed analysis of one of these mycobacteriophage (PDRPv)...
March 15, 2018: Canadian Journal of Microbiology
Céline Ronin, David Mendes Costa, Joana Tavares, Joana Faria, Fabrice Ciesielski, Paola Ciapetti, Terry K Smith, Jane MacDougall, Anabela Cordeiro-da-Silva, Iain K Pemberton
The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation...
2018: PloS One
Jinxu Gao, Adelphe Mfuh, Yuka Amako, Christina M Woo
Many therapeutics elicit cell-type specific polypharmacology that is executed by a network of molecular recognition events between a small molecule and the whole proteome. However, measurement of the structures that underpin the molecular associations between the proteome and even common therapeutics, such as the nonsteroidal anti-inflammatory drugs (NSAIDs), is limited by the inability to map the small molecule interactome. To address this gap, we developed a platform termed small molecule interactome mapping by photoaffinity labeling (SIM-PAL) and applied it to the in cellulo direct characterization of specific NSAID binding sites...
March 15, 2018: Journal of the American Chemical Society
Yan Zhang, Zhongyuan Huang, Letao Wang, Chunming Wang, Changde Zhang, Thomas E Wiese, Guangdi Wang, Kevin Eugene Riley, Zhe Wang
This work aims to face the challenge of monitoring small molecule drugs accurately and rapidly for point-of-care (POC) diagnosis in current clinical settings. Overdose of acetaminophen (AP), a commonly used OTC analgesic drug, has been determined to be a major cause of acute liver failure in the US and the UK. However, there is no rapid and accurate detection method available for this drug in the emergency room. The present study examined an AP sensing strategy that relies on a previously unexplored strong interaction between AP and the arginine (Arg) molecule...
March 15, 2018: Analytical Chemistry
Stephan R Bohl, Lars Bullinger, Frank G Rücker
The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes...
March 15, 2018: Expert Review of Hematology
Jing Ruan, Ying Wang, Fang Li, Renbing Jia, Guangming Zhou, Chunlin Shao, Liqi Zhu, Malin Cui, Da-Peng Yang, Shengfang Ge
Combination of drug chemotherapy and ray radiation is the main solution for treating patients with advanced colorectal carcinoma, but the toxicity and adverse effects caused in the surrounding normal tissues and the radio resistance in tumor site will severely influence its therapeutic effect. Nano radiosensitizer is an ideal choice for improving the tumor radiotherapy effects thanks to its high degree of tumor tissue uptake and secondary electrons productivity. Graphene quantum dots (GQDs) have good oxidative stress response and significantly high phototoxicity, and are regarded as a potential nano radiosensitizer...
March 15, 2018: ACS Applied Materials & Interfaces
Haeree Park, Yeongkyu Choi, M T Jeena, Eungjin Ahn, Yuri Choi, Myeong-Gyun Kang, Chae Gyu Lee, Tae-Hyuk Kwon, Hyun-Woo Rhee, Ja-Hyoung Ryu, Byeong-Su Kim
Owing to the unique advantages of combining the characteristics of hydrogels and nanoparticles, nanogels are actively investigated as a promising platform for advanced biomedical applications. In this work, a self-cross-linked hyperbranched polyglycerol nanogel is synthesized using the thiol-disulfide exchange reaction based on a novel disulfide-containing polymer. A series of structural analyses confirm the tunable size and cross-linking density depending on the type of polymer (homo- or copolymer) and the amount of reducing agent, dithiothreitol, used in the preparation of the nanogels...
March 15, 2018: Macromolecular Bioscience
Juan Li, Yang Du, Zhenqi Jiang, Yuchen Tian, Nianxiang Qiu, Yinjie Wang, Muhammad Zubair Lqbal, Menying Hu, Ruifen Zou, Lijia Luo, Shiyu Du, Jie Tian, Aiguo Wu
Due to the molecular and cellular heterogeneity of glioma, discovery of novel targeted sites and ligands for glioma imaging and therapy remains challenging. Neuropeptide Y (NPY) Y1 receptors (Y1 Rs) are highly over expressed in various brain tumors including glioma, and can serve as potential targeting sites for glioma imaging and therapy. Here, we show by in vivo fluorescent imaging that a highly selective Y1 R ligand, [Asn6 , Pro34 ] NPY (AP-NPY), facilitated circumvention of the blood brain barrier (BBB) by nanomicelles specifically targeting glioma...
March 15, 2018: Nanoscale
Wei Sun, Ju-Dong Luo, Hua Jiang, Dayue Darrel Duan
Tumor cells produce and secrete more nucleic acids, proteins and lipids than normal cells. These molecules are transported in the blood or around the cells in membrane-encapsulated exosomes. Tumor-derived or tumor-associated exosomes (usually 30-100 nm in diameter) contain abundant biological contents resembling those of the parent cells along with signaling messengers for intercellular communication involved in the pathogenesis, development, progression, and metastasis of cancer. As these exosomes can be detected and isolated from various body fluids, they have become attractive new biomarkers for the diagnosis and prognosis of cancer...
March 15, 2018: Acta Pharmacologica Sinica
Ekaterina Turlova, Zhong-Ping Feng, Hong-Shuo Sun
Stroke is one of the major causes of mortality and morbidity worldwide, yet novel therapeutic treatments for this condition are lacking. This review focuses on the roles of the transient receptor potential melastatin 2 (TRPM2) ion channels in cellular damage following hypoxia-ischemia and their potential as a future therapeutic target for stroke. Here, we highlight the complex molecular signaling that takes place in neurons, glial cells and the blood-brain barrier following ischemic insult. We also describe the evidence of TRPM2 involvement in these processes, as shown from numerous in vitro and in vivo studies that utilize genetic and pharmacological approaches...
March 15, 2018: Acta Pharmacologica Sinica
Ming-Xing Zhang, Shan-Shan Hong, Qing-Qing Cai, Meng Zhang, Jun Chen, Xiao-Yan Zhang, Cong-Jian Xu
Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer...
November 2018: Drug Delivery
Benjamin L Solomon, Ignacio Garrido-Laguna
The advent of immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4) has resulted in unprecedented long-term remissions of unresectable cancers. The efficacy of checkpoint inhibitors was recently demonstrated in gastrointestinal malignancies with mismatch repair deficiencies (dMMR). Pembrolizumab became the first tissue-agnostic US FDA-approved drug based on the presence of the predictive biomarker dMMR. In addition, the FDA in 2017 approved pembrolizumab for PD-L1-positive advanced gastric cancer in third-line and second-line hepatocellular therapy...
March 15, 2018: Future Oncology
Sarunya Tuntiyasawasdikul, Ekapol Limpongsa, Napaphak Jaipakdee, Bungorn Sripanidkulchai
RATIONAL: Phytoestrogens have been found to delay signs of skin aging in post-menopausal women, in a way similar to the effects of estrogens. Diarylheptanoids from a rhizome of traditional Thai herb named Curcuma comosa is considered to be a novel class of phytoestrogens. OBJECTIVES: The aims of this study were to prepare effective topical films using mixed types and vary ratios of hydrophobic (Eudragit RL, Eudragit RS, and Eudragit NE) and hydrophilic polymer (hydroxylpropyl methycellulose, HPMC) with Transcutol as a permeation enhancer for delivery of diarylheptanoids to improve signs of skin aging in post-menopausal women...
March 15, 2018: Drug Development and Industrial Pharmacy
Yingying Liu, Yudiao Huang, Yueyue Xu, Peng Qu, Minghua Wang
Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary reperfusion. Memantine is a licensed drug providing clinically relevant efficacy in patients with Alzheimer's disease. However, little information is known regarding its effects on brain endothelial permeability. In this study, we investigated the effects of memantine on endothelial permeability and the underlying mechanisms in an ischemia-reperfusion (I/R) injury model in primary human brain microvascular endothelial cells...
March 15, 2018: IUBMB Life
Charles K Davis, Sreekala S Nampoothiri, G K Rajanikant
The constant failure of single-target drug therapies for ischemic stroke necessitates the development of novel pleiotropic pharmacological treatment approaches, to effectively combat the aftermath of this devastating disorder. The major objective of our study involves a multi-target drug repurposing strategy to stabilize hypoxia-inducible factor-1 α (HIF-1α) via a structure-based screening approach to simultaneously inhibit its regulatory proteins, PHD2, FIH, and pVHL. Out of 1424 Food and Drug Administration (FDA)-approved drugs that were screened, folic acid (FA) emerged as the top hit and its binding potential to PHD2, FIH, and pVHL was further verified by re-docking, molecular dynamics (MD) simulation and by Drug Affinity Responsive Target Stability (DARTS) assay...
March 14, 2018: Molecular Neurobiology
Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2A R) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy...
March 14, 2018: Protein & Cell
Daniel J Ellenberger, Dave A Miller, Sandra U Kucera, Robert O Williams
Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space...
March 14, 2018: AAPS PharmSciTech
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