Trends in Modern Drug Discovery.

Drugs discovered by the pharmaceutical industry over the past 100 years have dramatically changed the practice of medicine and impacted on many aspects of our culture. For many years, drug discovery was a target- and mechanism-agnostic approach that was based on ethnobotanical knowledge often fueled by serendipity. With the advent of modern molecular biology methods and based on knowledge of the human genome, drug discovery has now largely changed into a hypothesis-driven target-based approach, a development which was paralleled by significant environmental changes in the pharmaceutical industry. Laboratories became increasingly computerized and automated, and geographically dispersed research sites are now more and more clustered into large centers to capture technological and biological synergies. Today, academia, the regulatory agencies, and the pharmaceutical industry all contribute to drug discovery, and, in order to translate the basic science into new medical treatments for unmet medical needs, pharmaceutical companies have to have a critical mass of excellent scientists working in many therapeutic fields, disciplines, and technologies. The imperative for the pharmaceutical industry to discover breakthrough medicines is matched by the increasing numbers of first-in-class drugs approved in recent years and reflects the impact of modern drug discovery approaches, technologies, and genomics.

Zebrafish bioassay-guided isolation of antiseizure compounds from the Cameroonian medicinal plant Cyperus articulatus L.

BACKGROUND: Epilepsy is a chronic neurological disorder affecting more than 50 million people worldwide, of whom 80% live in low- and middle-income countries. Due to the limited availability of antiseizure drugs (ASDs) in these countries, medicinal plants are the first-line treatment for most epilepsy patients. In Cameroon, a decoction of Cyperus articulatus L. rhizomes is traditionally used to treat epilepsy. PURPOSE: The aim of this study was to identify and isolate the active compounds responsible for the antiseizure activity of C. articulatus in order to confirm both its traditional medicinal usage and previous in vivo studies on extracts of this plant in mouse epilepsy models. METHODS: The dried rhizomes of C. articulatus were extracted with solvents of increasing polaritie (hexane, dichloromethane, methanol and water). A traditional decoction and an essential oil were also prepared. These extracts were evaluated for antiseizure activity using a larval zebrafish seizure model with seizures induced by the GABAA antagonist pentylenetetrazole (PTZ). The hexane extract demonstrated the highest antiseizure activity and was therefore selected for bioassay-guided fractionation. The isolated bioactive compounds were characterized by classical spectroscopic methods. Since they were found to be volatile, they were quantified by GC-FID. In addition, the absorption of the active compounds through the gastrointestinal tract and the blood-brain barrier was evaluated using a hexadecane and a blood-brain barrier parallel artificial membrane permeability assays (HDM-PAMPA and PAMPA-BBB). RESULTS: The hexane extract of C. articulatus exhibited the highest antiseizure activity with a reduction of 93% of PTZ-induced seizures, and was therefore subjected to bioassay-guided fractionation in order to isolate the active principles. Four sesquiterpenoids were identified as cyperotundone (1), mustakone (2), 1,2-dehydro-α-cyperone (3) and sesquichamaenol (4) and exhibited significant antiseizure activity. These volatile compounds were quantified by GC in the hexane extract, the essential oil and the simulated traditional decoction. In addition, the constituents of the hexane extract including compounds 1 and 2 were found to cross the gastrointestinal barrier and the major compound 2 crossed the blood-brain barrier as well. CONCLUSION: These results highlight the antiseizure activity of various sesquiterpene compounds from a hexane extract of C. articulatus dried rhizomes and support its use as a traditional treatment for epilepsy.

Setting Our Sights on Infectious Diseases.

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

The Foundation for the National Institutes of Health Biomarkers Consortium: Past Accomplishments and New Strategic Direction.

The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium (BC) is a public-private partnership that aims to facilitate drug development with biomarkers across a range of therapeutic areas. The BC is organized to address specific precompetitive biomarker projects, giving participating stakeholders a role in the design and conduct of projects and making the results freely public. Ultimately, the goals of the BC are to accelerate the development of new medicines, inform regulatory decision making, and improve patient care. Here, we describe how the BC works and briefly highlight its accomplishments. The BC has had many notable successful biomarker projects in the past 12 years, including I-SPY2, which has improved clinical trials and biomarker use for breast cancer, and an evidentiary framework for biomarker qualification. Recently, the BC has undergone a strategic expansion of its scope to include related drug development tools along the lines of the Biomarkers, Endpoints, and other Tools (BEST) resource.