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Drug Discovery Today

Aleksandr Ianevski, Petter I Andersen, Andres Merits, Magnar Bjørås, Denis Kainov
Broad-spectrum antivirals (BSAs) are agents that inhibit replication of several human viruses. Here, we review 108 approved, investigational, and experimental BSAs, for which safety profiles in humans are available. The most effective and tolerable BSAs could reinforce the arsenal of available antiviral therapeutics pending the results of further pre-clinical and clinical studies.
April 10, 2019: Drug Discovery Today
Fatemeh Vahdat Lasemi, Maryam Mahjoubin Tehran, Seyed Hamid Aghaee-Bakhtiari, Amin Jalili, Mahmoud Reza Jaafari, Amirhossein Sahebkar
Dyslipidemia is one of the major but modifiable risk factors for atherosclerotic cardiovascular disease (ACVD). Despite the accessibility of statins and other lipid-lowering drugs, the burden of ACVD is still high globally, highlighting the need for new therapeutic approaches. Nucleic acid-based technologies, including antisense oligonucleotides (ASOs), small interfering (si)RNAs, miRNAs, and decoys, are emerging therapeutic modalities for the treatment of ACVD. These technologies aim to degrade gene mRNA transcripts to decrease the levels of atherogenic lipoproteins...
April 10, 2019: Drug Discovery Today
Lucia Fusani, Alvaro Cortes Cabrera
Malaria affects a population of over 200 million people worldwide. New drugs are needed because of widespread resistance, and the hunt for such drugs involves a coordinated research effort from the scientific community. The release of the Tres Cantos Antimalarial Set (TCAMS) in 2010 represented a landmark in the field of collaborative drug discovery for malaria. This set of >13 000 molecules with confirmed activity against several strains of Plasmodium falciparum was publicly released with the goal of fostering additional research beyond the GlaxoSmithKline (GSK) network of collaborators...
April 10, 2019: Drug Discovery Today
Danilo Correddu, Ivanhoe K H Leung
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The exact cause(s) of PD is not well understood, although genetic mutations are associated with some forms of the disease. Many of these mutations, in particular those that are found in LRRK2, DJ1, PINK1, and Parkin, are linked to the deregulation of mRNA translation, suggesting that this process is important for the onset of PD. Herein, we highlight recent studies that provide insights into the molecular mechanisms that relate mRNA translation to PD...
April 8, 2019: Drug Discovery Today
Hovhannes J Gukasyan, Shumet Hailu, Thomas K Karami, Richard Graham
The estimation of ocular pharmacokinetics (PK) in various eye tissues is limited because of sampling challenges. Computational modeling and simulation tools underpinning the elucidation of drug access routes and prediction of ocular exposure are essential for the mechanistic assessment of biopharmaceutics in the eye. Therefore, theoretical and experimental evaluation of ocular absorption and transit models is necessary. Biopharmaceutical parameter sensitivity analysis based on permeability and drug dose illustrates utility in ocular drug delivery assessment, which could have innovative and cost-saving impacts on ophthalmic product development and therapeutic bioequivalence (BE) evaluations...
April 5, 2019: Drug Discovery Today
Andrew J Urquhart, Anne Z Eriksen
Diseases of the retina cause vision loss and blindness, which have a profound impact on an individual's quality of life. The number of therapies available to treat retinal diseases is limited. Nanoparticle (NP)-based medicines represent one strategy to expand both the number of available therapies and the range of retinal diseases treated. Liposomes, phospholipid vesicles that frequently contain cholesterol and/or modified surface chemistries, have already had minor success in retinal disease treatment and hold significant promise...
April 5, 2019: Drug Discovery Today
Erica L Fletcher, Anna Y Wang, Andrew I Jobling, Matthew V Rutar, Ursula Greferath, Ben Gu, Kirstan A Vessey
Age-related macular degeneration and glaucoma are the commonest causes of irreversible vision loss in industrialized countries. The purine ATP is known to regulate a range of cellular functions in the retina via its action on P2 receptors, especially the P2X7 receptor. Although agents that attenuate P2X7 receptor function have been in development for many years, no compound is currently approved for the treatment of eye disease. However, newer compounds that cross the blood-brain barrier could have potential to reduce vision loss...
April 4, 2019: Drug Discovery Today
Nabeela Dulull, Faith Kwa, Narin Osman, Uma Rai, Bilal Shaikh, Thilini R Thrimawithana
Diabetic retinopathy (DR) is a microvascular complication of diabetes and is the leading cause of vision loss in people with diabetes. The current treatments do not target early stages of disease or impede disease progression. Therefore, the identification of new therapeutic targets, the development of novel therapies targeting early stages of the disease and accurate models that simulate pathological characteristics of this disorder are crucial. This review provides an overview of the pathological mechanisms underlying the development of DR, highlighting the recent advances in current and emerging treatments for DR...
April 4, 2019: Drug Discovery Today
Jae Hwan Jung, J Jeremy Chae, Mark R Prausnitz
The suprachoroidal space (SCS), a potential anatomical space between the sclera and choroid, is a novel route for drug delivery targeting the chorioretinal layers of the eye. The safety and efficacy of SCS drug delivery have been shown in multiple clinical trials. Recent studies have developed methods for more precise targeting within the SCS at sites of action at the posterior pole (e.g., macula), near the limbus (e.g., ciliary body), and throughout the SCS using iontophoresis, swollen hydrogels, high-density particle emulsions, highly viscous and non-Newtonian fluids, and microstents...
April 3, 2019: Drug Discovery Today
Shanrong Zhao
Alternative splicing, hereafter referred to as AS, is an essential component of gene expression regulation that contributes to the diversity of proteomes. Recent developments in RNA sequencing (RNA-seq) technologies, combined with the advent of computational tools, have enabled transcriptome-wide studies of AS at an unprecedented scale and resolution. RNA mis-splicing can cause human disease, and to target alternative splicing has led to the development of novel therapeutics. Splice variants diversify the repertoire of biomarkers and functionally contribute to drug resistance...
April 3, 2019: Drug Discovery Today
Kambez H Benam, Siobhan Gilchrist, Andre Kleensang, Ani B Satz, Catherine Willett, Qiang Zhang
The Health Law, Policy & Ethics Project at Emory University School of Law and the Human Toxicology Project Consortium of the Humane Society of the United States co-sponsored a symposium on October 23, 2017, to showcase innovations using human-based in silico and in vitro models for drug and device discovery. The goal of the symposium was to introduce researchers and students to exciting new tools and possible future careers that will increase understanding of disease and improve the search for effective therapeutics, while reducing reliance on animal testing...
April 3, 2019: Drug Discovery Today
Fredrik Bergström, Bo Lindmark
The eventual candidate drug (CD) is often already synthesized during early drug discovery but not nominated until much later. To facilitate the rapid identification of a potential CD, a thoroughly worked-out CD target profile (CDTP) with criteria acceptable for the disease target product profile (TPP) is required at the start of lead generation (LG). In addition to driving the compound property optimization, the preclinical project team has to understand the ultimate goal to be able to rapidly identify and progress a potential CD...
April 1, 2019: Drug Discovery Today
Fang Yu, Deepak Choudhury
Bioprinting is a revolutionary technology to assemble scaffolds for growing tissues. Microfluidic organs-on-a-chip is a useful platform with widespread applications mainly in drug screening and pathological studies. Organ-on-a-chip models are created to recapitulate the structural, microenvironmental and physiological functions of human organs. Recently, bioprinting has been applied to fabricate organ-on-a-chip models owing to its ability to print multiple materials and cell types simultaneously with good spatial resolution and reproducibility...
March 30, 2019: Drug Discovery Today
Deepali Jhamb, Michal Magid-Slav, Mark R Hurle, Pankaj Agarwal
Genome-wide association studies (GWAS) have made considerable progress and there is emerging evidence that genetics-based targets can lead to 28% more launched drugs. We analyzed 1589 GWAS across 1456 pathways to translate these often imprecise genetic loci into therapeutic hypotheses for 182 diseases. These pathway-based genetic targets were validated by testing whether current drug targets were enriched in the pathway space for the same indication. Remarkably, 30% of diseases had significantly more targets in these pathways than expected by chance; the comparable number for GWAS alone (without pathway analysis) was zero...
March 29, 2019: Drug Discovery Today
Yosra Agban, Sachin S Thakur, Odunayo O Mugisho, Ilva D Rupenthal
The periocular space is a promising alternative route for the delivery of drugs to the posterior eye segment, especially when treating conditions in the outer ocular layers. In this review, we discuss the different periocular routes as well as the physiological barriers and elimination mechanisms limiting drug bioavailability at the back of the eye. We then highlight various types of depot formulation, including particulate delivery systems, semisolid formulations, and implants, used to increase the contact time with the ocular tissues...
March 28, 2019: Drug Discovery Today
Alicia Arranz-Romera, Sergio Esteban-Pérez, David Garcia-Herranz, Alba Aragón-Navas, Irene Bravo-Osuna, Rocio Herrero-Vanrell
Neurodegenerative diseases affecting the posterior segment of the eye are one of the major causes of irreversible blindness worldwide. The pathogenesis of these retinal pathologies is characterized by a multifactorial etiology, involving the complex interaction of different apoptotic mechanisms, suggesting that effective treatments will require a multimodal approach. Thus, combination therapy based on the potential synergistic activities of drugs with different mechanisms of action is currently receiving considerable attention...
March 27, 2019: Drug Discovery Today
Zahra Karami, Mohammad Reza Saghatchi Zanjani, Mehrdad Hamidi
Despite enormous efforts, treatment of CNS diseases remains challenging. One of the main issues causing this situation is limited CNS access for the majority of drugs used as part of the therapeutic regimens against life-threatening CNS diseases. Regarding the inarguable position of the nanocarrier systems in neuropharmacokinetic enhancement of the CNS drugs, this review discusses the latest findings on nanoemulsions (NEs) as one of the most promising candidates of this type, to overcome the challenges of CNS drug delivery...
March 23, 2019: Drug Discovery Today
Marjolein J A Weerts, Stefan Sleijfer, John W M Martens
Somatic variation in mitochondrial DNA (mtDNA) has been described in primary breast tumors, including single-nucleotide variants and variation in the number of mtDNA molecules per cell (mtDNA content). However, there is currently a gap in the knowledge on the link between mitochondrial variation in breast cancer cells and their phenotypic behavior (i.e., tumorigenesis) or outcome. This review focuses on recent findings on mtDNA content and mtDNA somatic mutations in breast cancer and the potential biological impact and clinical relevance...
March 22, 2019: Drug Discovery Today
Martijn Kerkhofs, Geert Bultynck, Tim Vervliet, Giovanni Monaco
Intracellular Ca2+ -flux systems located at the ER-mitochondrial axis govern mitochondrial Ca2+ balance and cell fate. Multiple yet incurable pathologies are characterized by insufficient or excessive Ca2+ fluxes toward the mitochondria, in turn leading to aberrant cell life or death dynamics. The discovery and ongoing molecular characterization of the main interorganellar Ca2+ gateways have resulted in a novel class of peptide tools able to regulate relevant protein-protein interactions (PPIs) underlying this signaling scenario...
March 22, 2019: Drug Discovery Today
Raphael Mietzner, Miriam Breunig
Glaucoma is one of the most common causes of blindness worldwide. Elevated intraocular pressure (IOP) is the major modifiable risk factor of the disease. Conventional therapy suffers from poor compliance, low bioavailability, and the lack of causative treatment options. To improve therapeutic success, it is crucial to identify major mediators of pathological changes associated with elevated IOP and to intervene at the molecular level. Here, we discuss relevant key functions of transforming growth factor-β2 (TGF-β2), connective tissue growth factor (CTGF), integrins, Rho-associated kinase (ROCK), and nitric oxide (NO) with regard to the onset of glaucoma, highlighting new drug delivery approaches for causative treatment...
March 21, 2019: Drug Discovery Today
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