First Images Produced of Herpes Virus Maneuver
A research team funded by the Biotechnology and Biological Sciences Research Council (BBSRC), has produced the first 3D image of a herpes virus protein interacting with an important part of human cellular machinery. The images increase the understanding of the key tactical maneuvers made by the herpes virus and give new insights into how to treat infections.
The herpes virus is an important target in pharmaceutical research as it is implicated in a host of diseases and ailments ranging from cold sores to more serious problems such as shingles and cancer. Itzhaki and co-workers have suggested that the herpes virus infection may be the trigger of the Alzheimer’s disease.
The researchers, led by Alexander Golovanov from the Univeristy of Manchester, UK, used NMR techniques to produce an image of the virus protein interacting with a mouse cellular protein. The image was used to generate a 3D model of the same herpes virus protein interacting with a human protein. The model showed the viral protein ‘piggybacking’ on the molecular machinery component inside the human cell (see image). With the assistance of biochemists, the group was then able to uncover the mechanism by which the viral and cellular proteins guide the genetic material outside of the cell nucleus, before it is used as the building blocks in the production of new viruses. The group then confirmed this relationship for two herpes virus proteins that infect monkeys.
The group intends to gain further insights into this mechanism. Golovanov told Future Medicinal Chemistry that, “Further detailed studies of a similar kind will be needed to understand how the whole viral mRNA export system works, only then we will know what is the unique weak point in the virus machinery which can be targeted with a specific drug.”
However, numerous questions remain to be answered, as Golovanov explained; “What is the 3D structure and functional role of other parts of ICP27 and its analogs in related herpes viruses? Where is the ‘weakest link’ in the virus-host interaction? The power of NMR spectroscopy, in combination with functional studies, can make a real impact in the field, and even contribute to the screening of compounds which specifically bind to the identified functional viral protein parts, contributing to the antiviral drug-design efforts. This is just the beginning.”
Sources: Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J. Pathol. 217(1), 131–138 (2009); Tunnicliffe RB, Hautbergue GM, Kalra P et al. Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57. PLoS Pathog. 7(1), e1001244 (2011).
Pharma Making Aggressive Changes to R&D Strategy, Claims Study
Pharmaceutical companies are increasingly being forced to adapt their approach to R&D as a result of expiring patent protection for prescription medicines and the low number of so-called blockbuster drugs in the development pipeline, claims a new study.
“The research-based drug industry, in the USA and globally, is not sitting still, but the question remains whether developers can bring enough new drugs to market at the pace needed to remain financially viable,” said Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development (CSDD), which compiled the study.
The Outlook 2011 report states that the average cost of developing a new drug has hit an all-time high of US$1.3 billion. Speaking at its release, Kaitin discussed the difficulty of predicting which products will become blockbusters – typically those generating annual revenues of at least $1 billion – and said the challenge to develop such products will be increasingly difficult in the coming years.
The study proposes various strategies that will help improve R&D productivity – these include increased reliance on translational science to assist the identification of disease targets; greater use of partnering with external service providers to share risks, reduce cycle times, lower costs and improve resource management; and greater use of sophisticated portfolio management techniques.
The report also outlines various near-term trends, including:
The US FDA will confront a serious public-health problem reaching critical mass: shortages of antibiotics, emergency drugs, anesthetic agents, drugs for cognitive disorders, and newer and improved pain medications;
Although more than half of all FDA-regulated clinical trials in 2010 were carried out outside the USA, sponsors will seek to decrease the number of countries hosting development activity in order to reduce global logistical and regulatory complexity;
The pharmaceutical and biotechnology industries will continue to dedicate resources to develop monoclonal antibodies (annual global sales of these products are currently approaching $40 billion);
Risk-sharing agreements to manage uncertain outcomes and costs (where drug companies and payers agree to share the risk associated with a newly approved product’s cost–effectiveness in clinical practice) will become more prevalent among private payers in the USA.
Source: Tufts Center’s Outlook 2011 report: http://csdd.tufts.edu/news/complete_story/pr_outlook_2011
Could Lung Inflammation Be Controlled by an Enzyme Inhibitor?
A research group from the Center for Inflammation, Translational and Clinical Lung Research and the Department of Physiology at Temple University (PA, USA), has indentified a potential therapeutic target for inflammation of the lungs. The team suggested, and confirmed using an animal model, that blocking the activation of the enzyme δ-PKC could protect the lungs from netrophil-mediated damage, which often results in out-of-control inflammation.
Acute respiratory distress syndrome (ARDS) leads to critically low levels of oxygen in the blood and usually occurs in those who are very ill or who already have life-threatening diseases or illnesses. It is, therefore, one of the leading causes of death in intensive and critical-care units and can often progress rapidly. Most patients who contract ARDS do not recover but those who do commonly suffer with lasting damage to their lungs or other serious health complaints. ARDS is currently very difficult to control as there are no specific drugs to treat it.
The research team hypothesized that controlling δ-PKC may reduce the risk of lung damage and illness. The group used rat models that had severe inflammation of the lungs or sepsis. The rats were split into two groups, one of which was given a placebo and the other a δ-PKC inhibitor directly. After 24 h the rats that had received the placebo exhibited lung injury and illness, breathing problems and lung tissue damage. The group that had received the δ-PKC inhibitor demonstrated significantly reduced evidence of lung distress suggesting that δ-PKC is indeed an important enzyme in ARDS.
The researchers believe this study could have implications in the treatment of lung inflammation not only as it opens up a potential treatment route for ARDS but it also reveals a mechanism that can be further explored in the development of specific and selective therapeutic agents.
Source: Kilpatrick LE, Standage SW, Li H et al. Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC). J. Leukoc. Biol. 89(1), 3–10 (2011).
Potential Target Identified for the Treatment of Atherosclerosis
A collaborative effort comprising of researchers from the University of Vienna, Austria, the Mount Sinai School of Medicine, USA, and the University of Bonn, Germany, has identified anaphylatoxin C5a, a protein released when the complement system is active, as a potential target for the treatment of atherosclerosis.
Atherosclerosis is a condition caused by the build-up of fatty materials, such as cholesterol, which leads to the thickening of the walls of arteries. This results in several health complaints and increases the likelihood of a heart attack or stroke. For years fitness levels, weight, diet and overall health have been implicated with such health risks but the study by the European–American team has now revealed the complement system as a new risk factor. The complement system is usually associated with immune responses, such as lupus, asthma or rheumatoid arthritis, but now is thought to have a role in cardiovascular disease.
Johan Wotja, lead author of the study, and colleagues treated white blood cells with anaphylatoxin C5a, which then responded by producing specific enzymes that dissolve the inner wall of atherosclerotic plaques in brain and coronary vessels. This leads to the plaques rupturing and breaking free, which then results in the blocking of the artery and increasing the risks of heart attacks and strokes.
This latest development could provide new leads in the treatment of atherosclerosis as well as other immune system participation diseases such as arthritis with anaphylatoxin C5a as the therapeutic target.
Source: Speidl WS, Kastl SP, Hutter R et al. The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. FASEB J. 25(1), 35–44 (2011).
Us$7.5 Million Awarded for Research into GabaB Modulators for Nicotine Addiction
The Scripps Research Institute (CA, USA) and the University of California, San Diego (UCSD; CA, USA) have been granted US$7.5 million over a 5-year period to develop novel positive GABAB modulators for the treatment of nicotine addiction. The funding from the NIH will be split with $5 million going to the two Scripps campuses and $2.5 million to UCSD.
The GABAB receptors, found in the CNS, mediate some of the actions of GABA including reward signals that are involved in drug addiction, such as nicotine dependence. Previous research at Scripps demonstrated that the first highly selective positive modulators of the GABAB receptors, developed at the institute, had the desired effects on nicotine dependence in animal models. The GABAB-positive modulators also had a better side-effect profile than other drugs that were undergoing similar investigations.
Patrick Griffin, chair of the Department of Molecular Therapeutics and Director of the Translational Research Institute at the Jupiter campus of Scripps told Future Medicinal Chemistry that, “the funding from the NIH will allow the research team to continue to optimize and refine our current lead compounds, which already show promise in models of nicotine dependence.”
The collaboration between UCSD and The Scripps Research Institute has one main goal, as Griffin explained: “Our hope is that we can improve the overall properties of the lead compounds in terms of selectivity, potency, functional selectivity and pharmacokinetics. If we are successful we hope to have a compound ready for IND filing during the grant period. Without these funds the project would likely not progress further and few companies are interested in licensing a compound at such an early stage. So this funding is very significant in terms of providing the means to translate the basic research findings made by the team.”
Source: TSRI-News Bi-Coastal Team Awarded $7.5 Million to Identify Potential Drug Candidates to Treat Nicotine Addiction: www.scripps.edu/newsandviews/e_20101220/nicotine.html
2011: The International Year of Chemistry
It has been announced that there will be a year-long celebration of all things chemistry this year under the unifying theme “Chemistry – our life, our future”. With the ultimate goal of more people gaining an interest in, and an appreciation of chemistry there will be a host of worldwide events for all ages and interests. The International Year of Chemistry 2011 (IYC 2011) will focus on the big challenges that chemistry faces now and in the future, including many medicinal chemistry-based themes. There is also a number of medicinal chemistry conferences that the IYC 2011 is promoting in its vast schedule of events, including the Third International Conference on Drug Discovery and Therapy in February and the 16th SCI-RSC Medicinal Chemistry Symposium in November. The year will conclude with a closing ceremony in December in Brussels.
Source: IYC 2011: www.chemistry2011.org