Drug Repurposing for Terminal-Stage Cancer Patients.

Am J Public Health. 2016 Jun;106(6):e3

Authors: Cvek B

PMID: 27153031 [PubMed - as supplied by publisher]

Repurposing drugs for treatment of tuberculosis: a role for non-steroidal anti-inflammatory drugs.

Br Med Bull. 2016 May 5;

Authors: Maitra A, Bates S, Shaik M, Evangelopoulos D, Abubakar I, McHugh TD, Lipman M, Bhakta S

Abstract
INTRODUCTION: The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment.
SOURCES OF DATA: Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies.
AREAS OF AGREEMENT: Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells.
AREAS OF CONTROVERSY: NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear.
GROWING POINTS: It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurposing molecules such as NSAIDs is a vital, low-risk strategy to combat the trend of rapidly increasing antibiotic resistance.

PMID: 27151954 [PubMed - as supplied by publisher]

Management and Treatment of Dengue and Chikungunya - Natural Products to the Rescue.

Comb Chem High Throughput Screen. 2016 May 6;

Authors: Suroowan S, Mahomoodally F, Ragoo L

Abstract
Neglected tropical diseases (NTDs) flourish mostly in impoverished developing nations of the world. It is estimated that NTDs plague up to 1 billion people every year thereby inducing a massive economic and health burden worldwide. Following explosive outbreaks mostly in Asia, Latin America, Europe and the Indian Ocean, two common NTDs namely, Chikungunya and Dengue both transmitted by an infected mosquito vector principally Aedes aegypti have emerged as a major public health threat. Given the limitations of conventional medicine in specifically targeting the Chikungunya and Dengue virus (CHIKV and DENV), natural products present an interesting avenue to explore in the quest of developing novel anti; mosquito, CHIKV and DENV agents. In this endeavor, a number of plant extracts, isolated compounds, essential oils and seaweeds have shown promising larvicidal and insecticidal activity against some mosquito vectors as well as anti CHIKV and DENV activity in-vitro. Other natural products that have depicted good potential against these diseases include; the symbiotic bacterial genus Wolbachia which can largely reduce the life span and infectivity of mosquito vectors and the marine Cyanobacterium Trichodesmium erythraeum which has shown anti-CHIKV activity at minimal cytotoxic level. The impetus of modern drug discovery approaches such as high throughput screening, drug repositioning, synthesis and computer-aided drug design will undeniably enhance the process of developing more stable lead molecules from natural products which have shown promising antiviral activity in-vitro.

PMID: 27151484 [PubMed - as supplied by publisher]

DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing.

BMC Bioinformatics. 2016;17(1):202

Authors: Issa NT, Kruger J, Wathieu H, Raja R, Byers SW, Dakshanamurthy S

Abstract
BACKGROUND: The targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation.
RESULTS: We present a systems polypharmacology platform entitled DrugGenEx-Net (DGE-NET). DGE-NET predicts empirical drug-target (DT) interactions, integrates interaction pairs into a multi-tiered network analysis, and ultimately predicts disease-specific drug polypharmacology through systems-based gene expression analysis. Incorporation of established biological network annotations for protein target-disease, -signaling pathway, -molecular function, and protein-protein interactions enhances predicted DT effects on disease pathophysiology. Over 50 drug-disease and 100 drug-pathway predictions are validated. For example, the predicted systems pharmacology of the cholesterol-lowering agent ezetimibe corroborates its potential carcinogenicity. When disease-specific gene expression analysis is integrated, DGE-NET prioritizes known therapeutics/experimental drugs as well as their contra-indications. Proof-of-concept is established for immune-related rheumatoid arthritis and inflammatory bowel disease, as well as neuro-degenerative Alzheimer's and Parkinson's diseases.
CONCLUSIONS: DGE-NET is a novel computational method that predicting drug therapeutic and counter-therapeutic indications by uniquely integrating systems pharmacology with gene expression analysis. DGE-NET correctly predicts various drug-disease indications by linking the biological activity of drugs and diseases at multiple tiers of biological action, and is therefore a useful approach to identifying drug candidates for re-purposing.

PMID: 27151405 [PubMed - in process]

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery.

Adv Drug Deliv Rev. 2016 May 2;

Authors: O'Connor G, Gleeson LE, Fagan-Murphy A, Cryan SA, O'Sullivan MP, Keane J

Abstract
Centuries since it was first described, tuberculosis (TB) remains a significant global public health issue. Despite ongoing holistic measures implemented by health authorities and a number of new oral treatments reaching the market, there is still a need for an advanced, efficient TB treatment. An adjunctive, host-directed therapy designed to enhance endogenous pathways and hence compliment current regimens could be the answer. The integration of drug repurposing, including synthetic and naturally occurring compounds, with a targeted drug delivery platform is an attractive development option. In order for a new anti-tubercular treatment to be produced in a timely manner, a multidisciplinary approach should be taken from the outset, including stakeholders from academia, the pharmaceutical industry, and regulatory bodies keeping the patient as the key focus. Pre-clinical considerations for the development of a targeted host-directed therapy are discussed here.

PMID: 27151307 [PubMed - as supplied by publisher]

Inhibition of Cholesterol Esterification in the Adrenal Gland by ATR101/PD132301-2, A Promising Case of Drug Repurposing.

Endocrinology. 2016 May;157(5):1719-1721

Authors: Kroiss M, Fassnacht M

PMID: 27149038 [PubMed - as supplied by publisher]

How Reliable Are Ligand-Centric Methods for Target Fishing?

Front Chem. 2016;4:15

Authors: Peón A, Dang CC, Ballester PJ

Abstract
Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict. The benchmark and a simple target prediction method to use as a performance baseline are available at http://ballester.marseille.inserm.fr/TF-benchmark.tar.gz.

PMID: 27148522 [PubMed]

Chloroquine-containing compounds: a patent review (2010 - 2014).

Expert Opin Ther Pat. 2015;25(9):1003-24

Authors: Njaria PM, Okombo J, Njuguna NM, Chibale K

Abstract
INTRODUCTION: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented.
AREAS COVERED: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions.
EXPERT OPINION: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7-chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy.

PMID: 26013494 [PubMed - indexed for MEDLINE]