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Medicinal Research Reviews

Jeffrey Yang, Longqin Hu
Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity...
September 14, 2018: Medicinal Research Reviews
Bharath Srinivasan, Sam Tonddast-Navaei, Ambrish Roy, Hongyi Zhou, Jeffrey Skolnick
Escherichia coli Dihydrofolate reductase is an important enzyme that is essential for the survival of the Gram-negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small-molecules resulting from their inability to cross the double membrane in Gram-negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug-resistance...
September 7, 2018: Medicinal Research Reviews
Alexander J Nielsen, James McNulty
The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity...
September 1, 2018: Medicinal Research Reviews
Wenyi Wu, Yanhui Yang, Hetian Lei
The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated endonucleases (Cas) has been utilized for genome editing with great accuracy and high efficiency in generating gene knockout, knockin, and point mutations in eukaryotic genomes. However, traditional CRISPR/Cas9 technology introduces double-stranded DNA breaks (DSBs) at a target locus as the first step to make gene corrections, which easily results in undesired mutations. Thus, it is necessary to develop new methods for correcting the unwanted mutations...
September 1, 2018: Medicinal Research Reviews
Chun-Ping Liu, You Hu, Ju-Chun Lin, Hua-Lin Fu, Lee Yong Lim, Zhi-Xiang Yuan
Kidney diseases have become a global public health problem. The application of kidney-targeted drug-delivery systems in the management of kidney diseases has profound transformative potential. Kidney-targeted drug delivery can reduce the undesired side effects of often potent drugs and enhance drug efficacy in alleviating the kidney disease. Here, we review the literature on the potential strategies for targeting drugs to the kidneys. Specifically, we provide a broad overview of the targeting vectors and targeting pathways for renal tubules and glomeruli, as well as how the unique structural features of the glomerulus and the receptor-mediated internalization pathways of the tubules allows for drug targeting...
August 22, 2018: Medicinal Research Reviews
Manoj Kumar Jaiswal
Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages...
August 12, 2018: Medicinal Research Reviews
Valeria Cernaro, Giuseppe Coppolino, Luca Visconti, Laura Rivoli, Antonio Lacquaniti, Domenico Santoro, Antoine Buemi, Saverio Loddo, Michele Buemi
Erythropoiesis is triggered by hypoxia and is strictly regulated by hormones, growth factors, cytokines, and vitamins to ensure an adequate oxygen delivery to all body cells. Abnormalities in one or more of these factors may induce different kinds of anemia requiring different treatments. A key player in red blood cell production is erythropoietin. It is a glycoprotein hormone, mainly produced by the kidneys, that promotes erythroid progenitor cell survival and differentiation in the bone marrow and regulates iron metabolism...
August 6, 2018: Medicinal Research Reviews
Peter J Cossar, Peter J Lewis, Adam McCluskey
There are 27 small molecule protein-protein interaction (PPI) modulators in Phase I, II, and III clinical trials targeting cancer, viruses, autoimmune disorders, and as immune suppression agents. Targeting PPIs as an antibiotic drug discovery strategy remains in relative infancy by comparison. However, a number of molecules are in development which target PPI within the replisome, divisome, transcriptome, and translatome are showing significant promise at the medicinal chemistry stage of drug development. Hence, the success of future PPI agents as antibiotics will build upon the techniques and design strategies of these molecules...
July 13, 2018: Medicinal Research Reviews
Ahmed Karam Farag, Eun Joo Roh
Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain...
June 27, 2018: Medicinal Research Reviews
Yuanyuan Shan, Binghe Wang, Jie Zhang
Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept...
September 2018: Medicinal Research Reviews
Xiao-Fei Shang, Susan L Morris-Natschke, Guan-Zhou Yang, Ying-Qian Liu, Xiao Guo, Xiao-Shan Xu, Masuo Goto, Jun-Cai Li, Ji-Yu Zhang, Kuo-Hsiung Lee
To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed...
September 2018: Medicinal Research Reviews
Martti Vaara
Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram-negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose-limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last-line defense...
September 2018: Medicinal Research Reviews
Abdullah Al Nahain, Vera Ignjatovic, Paul Monagle, John Tsanaktsidis, Vito Ferro
Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well-publicized contamination scandal, into the development of alternative anticoagulants derived from non-animal and/or totally synthetic sources that mimic the structural features and properties of heparin...
September 2018: Medicinal Research Reviews
Xiaoyun Lu, Lei Yu, Zhang Zhang, Xiaomei Ren, Jeff B Smaill, Ke Ding
Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFRT790M ...
September 2018: Medicinal Research Reviews
Poonam, Yash Gupta, Nikesh Gupta, Snigdha Singh, Lidong Wu, Bhupender Singh Chhikara, Manmeet Rawat, Brijesh Rathi
Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i...
September 2018: Medicinal Research Reviews
Pei Zhang, Jilian Wu, Fengmei Xiao, Dujuan Zhao, Yuxia Luan
Increasing numbers of disulfide linkage-employing polymeric drug carriers that utilize the reversible peculiarity of this unique covalent bond have been reported. The reduction-sensitive disulfide bond is usually employed as a linkage between hydrophilic and hydrophobic polymers, polymers and drugs, or as cross-linkers in polymeric drug carriers. These polymeric drug carriers are designed to exploit the significant redox potential difference between the reducing intracellular environments and relatively oxidizing extracellular spaces...
September 2018: Medicinal Research Reviews
Yuan Quan, Zhong-Yi Wang, Xin-Yi Chu, Hong-Yu Zhang
In the modern drug discovery pipeline, identification of novel drug targets is a critical step. Despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. This fact is partially responsible for the situation of "more investments, fewer drugs" in the pharmaceutical industry. A series of recent researches revealed that successfully targeted genes share some common evolutionary and genetic features, which means that the knowledge accumulated in modern evolutionary biology and genetics is very helpful to identify potential drug targets and to find new drugs as well...
September 2018: Medicinal Research Reviews
Paolo Spallarossa, Giovanni Meliota, Claudio Brunelli, Eleonora Arboscello, Pietro Ameri, Christian Cadeddu Dessalvi, Francesco Grossi, Martino Deidda, Donato Mele, Matteo Sarocchi, Andrea Bellodi, Rosalinda Madonna, Giuseppe Mercuro
Cancer immunotherapy has become a well-established treatment option for some cancers after the development of a family of drugs targeting the so-called immune checkpoints, such as CTLA4 and PD-1 with PD-L1. These co-receptors/ligands inhibit the activation of T-cell, thus preventing an excessive inflammatory response. Tumors exploit these pathways to induce immune tolerance to themselves. Thus, the main effect of checkpoint-blocking drugs is to awake an immune response primarily directed against cancer cells...
September 2018: Medicinal Research Reviews
Mojtaba Khajeh Alizadeh Attar, Muhammad Ayaz Anwar, Mahsa Eskian, Mahsa Keshavarz-Fathi, Sangdun Choi, Nima Rezaei
Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders...
September 2018: Medicinal Research Reviews
Přemysl Mladěnka, Lenka Applová, Jiří Patočka, Vera Marisa Costa, Fernando Remiao, Jana Pourová, Aleš Mladěnka, Jana Karlíčková, Luděk Jahodář, Marie Vopršalová, Kurt J Varner, Martin Štěrba
Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases...
July 2018: Medicinal Research Reviews
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