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Current Opinion in Pharmacology

Bei Shi Lee, Kevin Pethe
In the field of tuberculosis drug development, the term 'promiscuous' was coined to collectively describe targets that repeatedly show up in whole-cell screenings. With the current climate leaning towards the exclusion of these targets in future drug screens, this review discusses and clarifies misconceptions surrounding this classification, the prospects of developing compounds targeting promiscuous targets, and their potential impact on tuberculosis drug development. The dominance of these targets in cell-based screens reflect not only bias introduced by experimental setup, but also some of the pathogen's greatest vulnerabilities...
July 13, 2018: Current Opinion in Pharmacology
Magdalena K Bielecka, Paul Elkington
Mycobacterium tuberculosis (Mtb) kills more humans than any other infection and drug resistant strains are progressively emerging. Whilst the successful development of new agents for multi-drug resistant Mtb represents a major step forward, this progress must be balanced against recent disappointments in treatment-shortening trials. Consequently, there is a pressing need to strengthen the pipeline of drugs to treat tuberculosis (TB) and develop innovative therapeutic regimes. Approaches that bridge diverse disciplines are likely to be required to provide systems that address the limitations of current experimental models...
July 7, 2018: Current Opinion in Pharmacology
J Magarian Blander, Gaetan Barbet
Live attenuated vaccines elicit stronger protective immunity than dead vaccines. Distinct PAMPs designated as vita-PAMPs signify microbial viability to innate immune cells. Two vita-PAMPs have been characterized: cyclic-di-adenosine-monophosphate (c-di-AMP) and prokaryotic messenger RNA (mRNA). c-di-AMP produced by live Gram-positive bacteria elicits augmented production of STING-dependent type-I interferon, whereas prokaryotic mRNA from live bacteria is detected by TLR8 enabling discrimination of live from dead bacteria...
June 8, 2018: Current Opinion in Pharmacology
Anastasia Koch, Helen Cox, Valerie Mizrahi
With an estimated incidence of 490000 cases in 2016, multidrug resistant tuberculosis (TB), against which key first-line anti-tuberculars are less efficacious, presents major challenges for global health. Poor treatment outcomes coupled with a yawning treatment gap between those in need of second-line therapy and those who receive it, underscore the urgent need for new approaches to tackle the scourge of drug-resistant TB. Against this background, significant progress has been made in understanding the complex biology of TB drug resistance and disease pathogenesis, and in establishing a pipeline for delivering new drugs and drug combinations...
June 6, 2018: Current Opinion in Pharmacology
Alice Harper, Katie L Flanagan
It is well established that vaccination does not affect males and females equally. For example, females generally mount greater antibody responses to vaccination than males, but also suffer more adverse events following vaccination, probably as a result of more robust immunity. Despite this, most researchers in the field of vaccinology do not take biological sex into account when conducting their studies. This omission is likely to lead to a loss of important information in terms of both reactogenicity and immunogenicity following vaccination as well as those suffering adverse events...
June 5, 2018: Current Opinion in Pharmacology
Umbreen Hafeez, Hui K Gan, Andrew M Scott
Since Nobel laureate Paul Ehrlich proposed the concept of magic bullet in 1906, Köhler and Milstein discovered Hybridoma technology in 1975, and Greg Winter pioneered the technique to humanize monoclonal antibodies in 1988, monoclonal antibodies have been successfully developed to treat medical illnesses. Monoclonal antibodies are effective treatments for inhibition of alloimmune reactivity, haematological malignancies, solid organ malignancies, viral illnesses and are also used as antiplatelet therapy. Their successful use in cancer and autoimmune diseases in humans have made them one of the fastest growing classes of new drugs approved for these indications in last few decades...
June 5, 2018: Current Opinion in Pharmacology
Burcu Temizoz, Etsushi Kuroda, Ken J Ishii
Innate immune sensing of nucleic acids derived from invading pathogens or tumor cells via pattern recognition receptors is crucial for mounting protective immune responses against infectious disease and cancer. Recently, discovery of tremendous amounts of nucleic acid sensors as well as identification of natural and synthetic ligands for these receptors revealed the potential of adjuvants targeting nucleic acid sensing pathways for designing efficacious vaccines. Especially, current data indicated that unique adjuvants targeting TLR9 and stimulator of interferon genes (STING)-dependent cytosolic nucleic acid sensing pathways along with the combinations of already existing adjuvants are promising candidates for this purpose...
June 2, 2018: Current Opinion in Pharmacology
Rob Hooft van Huijsduijnen, Timothy Nc Wells
Over the past decade, new high-throughput phenotypic assays with malaria parasites have been developed, and these were used to screen millions of compounds. This effort, as well as improving older chemical scaffolds and optimising compounds against both known and new drug targets has resulted in the discovery of exciting new pipeline drug candidates that are now being evaluated in a number of clinical trials. In addition, the pitfalls and opportunities from this experience has led to a better definition of the optimal target compound and product profiles for new antimalarials, including medicines that treat uncomplicated or severe malaria, provide chemoprevention, or stop disease transmission, covering all stages of the parasite...
May 31, 2018: Current Opinion in Pharmacology
Mateusz Legut, Andrew K Sewell
Cancer immunotherapy, focused on harnessing and empowering the immune system against tumours, has transformed modern oncology. One of the most promising avenues in development involves using genetically engineered T-cells to target cancer antigens via specific T-cell receptors (TCRs). TCRs have a naturally low affinity towards cancer-associated antigens, and therefore show scope for improvement. Here we describe approaches to procure TCRs with enhanced affinity and specificity towards cancer, using protein engineering or selection of natural TCRs from unadulterated repertoires...
May 29, 2018: Current Opinion in Pharmacology
Brandi Johnson-Weaver, Hae Woong Choi, Soman N Abraham, Herman F Staats
Mast cells are an important cell type of the innate immune system that when activated, play a crucial role in generating protective innate host responses after bacterial and viral infection. Additionally, activated mast cells influence lymph node composition to regulate the induction of adaptive immune responses. The recognition that mast cells play a beneficial role in host responses to microbial infection and induction of adaptive immunity has provided the rationale to evaluate mast cell activators for use as antimicrobials or vaccine adjuvants...
May 26, 2018: Current Opinion in Pharmacology
Christina L Grek, Zhi Sheng, Christian C Naus, Wun Chey Sin, Robert G Gourdie, Gautam G Ghatnekar
Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding...
May 24, 2018: Current Opinion in Pharmacology
Alyson P Black, Anand S Mehta
Hepatocellular carcinoma (HCC) is the 5th most common cancer, but the 3rd leading cause of cancer death globally with approximately 700,000 fatalities annually. The severity of this cancer arises from its difficulty to detect and treat. The major etiologies of HCC are liver fibrosis or cirrhosis from chronic viral infections, as well as metabolic conditions. Since most cases arise from prior pathologies, biomarker surveillance in high-risk individuals is an essential approach for early detection and improved patient outcome...
May 14, 2018: Current Opinion in Pharmacology
T C Guillette, Thomas W Jackson, Scott M Belcher
The physiological actions of estrogens are primarily mediated by the nuclear hormone receptors estrogen receptor alpha (ERα) and beta (ERβ). Activities of these nuclear steroid hormone receptors in etiology and progression of many hormone-responsive cancers are well-established, yet the specific role of each receptor, and their various expressed isoforms, in estrogen-responsive cancers remains unclear. Recent advances in nuclear receptor profiling, characterization of expressed splice variants, and the availability of new experimental cancer models, has extended the understanding of the complex interplay between the differentially expressed nuclear estrogen receptors...
May 14, 2018: Current Opinion in Pharmacology
Jamie N Mills, Alex C Rutkovsky, Antonio Giordano
Several mechanisms of resistance have been identified, underscoring the complex nature of estrogen receptor (ER) signaling and the many connections between this pathway and other essential signaling pathways in breast cancer cells. Many therapeutic targets of cell signaling and cell cycle pathways have met success with endocrine therapy and remain an ongoing area of investigation. This review focuses on two major pathways that have recently emerged as important opportunities for therapeutic intervention in endocrine resistant breast tumors: PI3K/AKT/mTOR cell signaling and cyclinD1/cyclin-dependent kinase 4/6 cell cycle pathways...
April 29, 2018: Current Opinion in Pharmacology
Olivia Manfrini, Peter Louis Amaduzzi, Edina Cenko, Raffaele Bugiardini
Prevalence of peripheral arterial disease in patients with coronary artery disease is considerably higher than in the general population. A graded increase in the risk of major cardiovascular events in a variety of clinical settings is associated with the number of arterial beds affected by peripheral arterial disease. This is not surprising, considering that both coronary artery disease and peripheral arterial disease are linked to a higher prevalence of cardiovascular risk factors and a greater incidence of atherosclerotic burden...
April 26, 2018: Current Opinion in Pharmacology
Vera P Mourits, Jac Chm Wijkmans, Leo Ab Joosten, Mihai G Netea
Recent studies have shown that upon certain vaccinations or infections human innate immune cells can undergo extensive metabolic and epigenetic reprogramming, which results in enhanced immune responses upon heterologous re-infection, a process termed trained immunity. Trained immunity has also been shown to be inappropriately activated in inflammatory diseases. This provides the potential for identifying novel therapeutic targets: potentiation of trained immunity could protect from secondary infections and reverse immunotolerant states, while inhibition of trained immunity might reduce excessive immune activation in chronic inflammatory conditions...
April 24, 2018: Current Opinion in Pharmacology
S Jeffrey Dixon, Peter Chidiac
No abstract text is available yet for this article.
June 2018: Current Opinion in Pharmacology
Marjolein P Baar, Eusebio Perdiguero, Pura Muñoz-Cánoves, Peter Lj de Keizer
Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals...
June 2018: Current Opinion in Pharmacology
Mario Cazzola, Maria Gabriella Matera
No abstract text is available yet for this article.
June 2018: Current Opinion in Pharmacology
Maria Gabriella Matera, Clive Page, Barbara Rinaldi
Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the β2-AR when activated, a subset of different intracellular responses can be triggered...
June 2018: Current Opinion in Pharmacology
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