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Molecular Flexibility Shown to Help Pharmaceutical Drugs Bind to Their Targets

Breakthrough could open up new directon when designing pharmaceutical drugs

By Sean Nealon

RIVERSIDE, Calif. (www.ucr.edu) — Scientists have discovered an alternative way to create a stronger binding between pharmaceutical drugs and the part of the body they are targeting – a development that can be used to fight a variety of diseases, including breast cancer.

The study published in the journal PLOS Computational Biology shows that flexible molecules, instead of rigid ones, as previously thought, can bind more effectively to the proteins causing the disease.

Being a tight binder is important for a molecule to be a good pharmaceutical drug. When designing a pharmaceutical drug, scientists typically make molecules – which are naturally flexible – rigid so that they can strongly bind, like a lock and key, with the disease causing protein in the body.

When molecules bind to their partners they usually decrease their flexibility which leads to the so-called entropy penalty. Having a large entropy penalty has been shown to be bad for creating a tight bindings. Scientists aim to reduce it so that the drug can stay on the target protein and alter its functional behavior for good. However, one key problem to this approach is that scientists are reaching the limit of how much rigidity can be produced in order to reduce entropy penalty and result in tighter binders.

Researchers, led by Wanli You, a graduate student at the University of California, Riverside, found that keeping the molecules flexible, as opposed to making them rigid, both reduced the entropy penalty and created a stronger binding.

One of the authors, Chia-en A. Chang, an associate professor of chemistry at UC Riverside, notes that: “This was really unexpected and opens up a new direction for designing pharmaceutical drugs”.

In order to discover this, the researchers examined the thermodynamic properties of different ligands binding to a promiscuous modular protein, Breast-cancer-gene 1 (BRCA1) C-terminal (BRCT). The authors used molecular dynamics simulations and a rigorous free energy calculation method to study ligands binding to BRCT, understand promiscuous molecular recognition and guide inhibitor design. Flexible ligands, the researchers found, may utilize multiple conformations in their bound states to keep good attractions with BRCT whilst also reducing entropy cost.

The research focused on breast cancer drugs, but the principles could be applied in drug development targeting other diseases and also in basic cell biology studies.

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Molecular Flexibility Shown to Help Pharmaceutical Drugs Bind to Their Targets

Needles that hit the right mark

New sensor could help anesthesiologists place needles for epidurals and other medical procedures.

Anne Trafton | MIT News Office

More than 13 million pain-blocking epidural procedures are performed every year in the United States. Although epidurals are generally regarded as safe, there are complications in up to 10 percent of cases, in which the needles are inserted too far or placed in the wrong tissue.

A team of researchers from MIT and Massachusetts General Hospital hopes to improve those numbers with a new sensor that can be embedded into an epidural needle, helping anesthesia doctors guide the needle to the correct location.

Currently, anesthesiologists must guide a four- to six-inch needle through multiple layers of tissue to reach the epidural space surrounding the spinal cord. They know when the needle has reached the right spot based on how the tissue’s resistance changes. However, some patients’ tissues vary from the usual pattern, which can make it more difficult to determine whether the needle is in the right place.

“The needle is placed essentially blindly,” says T. Anthony Anderson, an anesthesiologist at MGH and an assistant professor at Harvard Medical School. “The needle can go too far or into the wrong tissue, which means the patient doesn’t get the positive effect that you want or is injured.”

In most cases, these complications lead to reduced effectiveness of the pain-killing drug, or an excruciating post-procedure headache. In rare cases in which the needle goes too far or into a blood vessel, a stroke or spinal cord injury can occur.

Distinguishing tissues

To improve the accuracy of epidural needle placement, Anderson teamed up with researchers at MIT’s Laser Biomedical Research Center, headed by Peter So, a professor of mechanical engineering and biological engineering.

So and MIT research scientist Jeon Woong Kang designed and tested several types of optical sensors that could be placed at the tip of an epidural needle and determined that the best is one that relies on Raman spectroscopy. This technique, which uses light to measure energy shifts in molecular vibrations, offers detailed information about the chemical composition of tissue. In this case, the researchers measured the concentrations of albumin, actin, collagen, triolein, and phosphatidylcholine to accurately identify different tissue layers.

This sensor, which the researchers described in the journal Anesthesiology, provides immediate feedback telling the anesthesiologist which tissue the needle is in. As an epidural needle is inserted, it passes through five layers — skin, fat, supraspinous ligament, interspinous ligament, and ligamentum flavum — before reaching the epidural space, which is the target. Beyond that space lies the dura mater, a stiff membrane that surrounds the spinal cord and cerebrospinal fluid.

“The sensor is continuously measuring Raman spectroscopy signals, which tells you the chemical composition of the tissue. From the chemical composition you can identify all tissue layers, from skin to spinal cord,” Kang says.

The team found that Raman spectroscopy could distinguish each of the eight tissue layers around the epidural space with 100 percent accuracy. Two other techniques that they tested, fluorescence and reflectance spectroscopy, could distinguish some layers but not all eight.

“Blind procedures”

The researchers have tested the sensor in pig tissue and now plan to do further animal studies before testing it in human patients. They also plan to reduce the diameter of the sensor slightly, from 2 millimeters, which is too large to fit in the most commonly used epidural needles, to 0.5 mm.

Jeanine Wiener-Kronish, chief of anesthesia and critical care at MGH, says this type of sensor could greatly improve safety for epidurals, as well as other procedures involving needles.

“The era of blind procedures is one we need to move away from, because we’re very interested in improving safety and quality,” says Wiener-Kronish, who was not involved in the research. “This sensor could allow us to take a fairly blind procedure and be able to get more information about where the needle is.”

The researchers have started a company, Medisight Corp., to continue developing the technology, which they believe could also be applied to medical procedures, such as cancer biopsies or injecting drugs into the joints, which can be difficult to do accurately. This commercialization effort is supported by MIT entrepreneurship programs, including the MIT Translational Fellows Program, MIT Venture Mentoring Service, and MIT Innovation Initiative. The team also received support from the National Science Foundation in the form of a Small Business Technology Transfer program grant.

In addition to So, Kang, and Anderson, authors of the paper include Tatyana Gubin, an MIT undergraduate, and Ramachandra Dasari, a principal research scientist in MIT’s Department of Chemistry.

MIT

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Needles that hit the right mark

Millions deprived of life saving antifungal medicines, report finds

Actor and GAFFI celebrity patron Rupert Everett declared that: “We have known for over 25 years that many people with AIDS and cancer do die of fungal complications. And death is avoidable with treatment. Why on earth are commonly used antifungal medicines not provided to everyone who needs them?”

Dr Glenda Gray, President and CEO of the African Medical Research Council and Professor of Pediatrics, Faculty of Health Sciences, at University of Witwatersrand, said: “In South Africa we are addressing the HIV epidemic squarely on with greatly increased provision of anti-retroviral drugs and expanding testing.

“Fungal diseases in AIDS have not received the priority they should have, although this is now changing with our national screening program for Cryptococci meningitis. Clearly ensuring antifungal agents are available to all is an key component in reducing deaths and illness across southern Africa."

Key findings:

• One of the critical drugs for fungal meningitis in AIDS (amphotericin B) is not available in 42 countries. The other key drug for fungal meningitis, flucytosine, is unavailable in at least 95 countries. Yet both have been available in Europe and the US for over 40 years. The World Health Organization recommends they be used together to bring down mortality from 100% to 25%. Fungal meningitis is the commonest form of meningitis in sub-Saharan Africa because of AIDS.

• The 25 -year old drug, fluconazole is available in all countries and itraconazole is unavailable in just five countries. However, being available is not enough – price also matters as patients pay for their care in many countries. The daily cost of fluconazole varied from <$1 to $31 and itraconazole from <$1 to $102. In South Africa, which has the largest AIDS burden in the world and a massive TB problem, itraconazole costs about £11.60 per day – unaffordable for most people there.

*Kneale M, Bartholomew JS, Davies E, Denning DW. Global Access to Antifungal Therapy and its Variable Cost. J Antimicrob Chemother. In press.

The University of Manchester

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Millions deprived of life saving antifungal medicines, report finds

New imaging platform tracks cancer progression

A new rapid fluorescent 3-D imaging system developed by UCL and Imperial College London scientists offers a non-invasive approach to accurately monitor tumour development in adult zebrafish.

Animal testing is an essential step in developing new drugs for diseases; however, the process usually involves invasive procedures with animals that must be euthanized. The new method, adapted from an imaging method called optical projection tomography (OPT), repeatedly images the same organisms, reducing the number of animals used in testing.

The MRC-funded scientists can now image and measure the growth of cancerous tumours and the associated development of growth-enabling blood vessels in live zebrafish which develop cancer in a way similar to humans. UCL is a world leader in zebrafish research with the largest and most comprehensive fish facility in the UK.

Dr Paul Frankel, UCL Division of Medicine, who led the cancer biology aspects of the project, said: “Zebrafish serve as animal models of liver and other cancers, developing a form of the disease genetically similar to human tumours. This, as well as their small size, quick reproduction and transparency – which is necessary for OPT imaging – makes zebrafish an ideal organism to study using this technique.”

Being able to track the stages of disease progression in a living organism means the team could also use the technique to monitor the effects of new anti-cancer drugs that aim to reduce tumour size.

Co-first author, Nicola Lockwood, also UCL Division of Medicine, said: “With the zebrafish model, we were able to directly visualise live progression of tumours within the context of a fully formed blood supply and immune system. This will be extremely important as we proceed to development of novel anti-cancer drugs.”

Essential to tumour development is angiogenesis, the process by which tumours generate their own blood vessels to deliver the nutrients that enable growth. This process also facilitates the spread of tumours to other parts of the body, usually resulting in poor patient prognosis and death.

In a preliminary study, the OPT system was used to image zebrafish over time during tumour progression, allowing the researchers to measure tumour size and the amount of blood vessels within the tumour.

The approach uses genetic fluorescence labelling techniques, which allow internal organs to be visualised through their emission of different colour light. In the study, zebrafish whose blood vessels were labelled with a red fluorescent protein were bred with zebrafish that grew liver tumours labelled with a green fluorescent protein when given a chemical compound called doxycycline.

As the offspring of these fish have both genes, when imaged, their blood vessels fluoresce red and the liver tumour fluoresces green.

“This technique has the advantage of being simple and robust,” said Professor Paul French, from the Department of Physics at Imperial, who led the development of OPT. “Unlike the other 3-D optical imaging techniques, it doesn’t rely on focused light, so it is relatively gentle on the organism being imaged. This makes it particularly good for imaging live animals across long timescales.”

The ability to perform studies over time allows researchers to assess disease progression in the same organism over spans of weeks to months. It is also able to yield high-resolution 3-D images at a fraction of the time and cost of other imaging techniques. In one study the team repeatedly imaged zebrafish expressing red fluorescent blood vessels over a period of five months.

Such longitudinal studies will enable research into potential long-term side effects of drug treatments including adverse reactions and the development of drug resistance.

“It’s well known that individuals can respond differently to the same drug treatment, therefore techniques such as ours could provide valuable information regarding disease progression and drug efficacy,” added Professor French.

The team are currently combining OPT with other techniques, such as fluorescence lifetime imaging, to map cell signalling processes. This could be used to monitor cell death, making it potentially useful to test chemotherapy drugs and identifying whether the drug is having unwanted side effects.

University College London

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New imaging platform tracks cancer progression

Treatment option for Alzheimer’s disease possible

Dr Brough said: “There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer’s disease worse.

“Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells.”

He added: “Until now, no drug has been available to target this pathway, so we are very excited by this result.

“However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don’t always faithfully replicate the human disease.

“Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.

“We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.”

Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said: “Testing drugs already in use for other conditions is a priority for Alzheimer’s Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.

“These promising lab results identify a class of existing drugs that have potential to treat Alzheimer’s disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer’s disease at this stage – studies in people are needed first.”

Fenamate NSAIDs inhibit the NLRP3 inflammasome and 2 protect against Alzheimer’s disease in rodent models, published in the journal Nature Communications. DOI: 10.1038/NCOMMS12504

Please note, this study is experimental and doctors do not prescribe Mefenamic Acid as a treatment for Alzheimer’s Disease. For queries about treatment and care, please contact Alzheimer’s Society on 0330 333 0804. or email [email protected]

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Treatment option for Alzheimer’s disease possible

The Medical Minute: The dangerous allure of performance-enhancing drugs

Imagine you dedicate your whole life to becoming the best in your chosen sport. You put in the work, make big sacrifices and finally make the Olympic team. You have a shot at a medal — and all the money, fame and influence that comes with it.

Then, someone offers you a magic pill with two guarantees — that you won’t get caught and that you’ll win everything. There’s just one catch: you’ll be dead within five years from the pill’s side effects.

Would you take it?

A popular 1995 survey of Olympic hopefuls found that more than 50 percent of those given that proposal said they’d do it, lending insight into why many of the world’s best athletes are tempted by performance-enhancing drugs, even when the risks are high.

“I think that really speaks to the mentality,” said Dr. Matthew Silvis, director of primary care sports medicine at Penn State Health Milton S. Hershey Medical Center. “They are not really thinking about life down the road because they are so wrapped up in the moment. This is their opportunity.”

The list of substances that can mean the difference between winning and not winning is long, and includes everything from testosterone and anabolic steroids to red-cell boosters, depending on the effect you want. The drugs act on the body to enhance athletic performance by increasing muscle mass or boosting the amount of blood and oxygen carried to muscles.

While football players are more likely to use steroids or testosterone to beef up, cyclists may be tempted by EPO, or erythropoietin, a drug designed to help patients in kidney failure, which some athletes use to increase their endurance.

“Doping is really something that is present in all sports,” Silvis said. “It depends on how much the governing body of that sport is looking for it.”

He said scientists behind performance-enhancing drugs work hard to create products that are more difficult to detect, with the latest frontier being alteration of a person’s genetics to be a better athlete.

“From an ethical perspective, sports should be about who is the most naturally gifted and who works the hardest, but sometimes it’s about who has the best scientist in their corner to give them the edge,” Silvis said.

Once the games are over, the leftover effects of doping can derail even the healthiest athlete’s system.

Those who take EPO can find their body creating so many red blood cells that they develop clots and pulmonary embolisms.

Weight lifters who use testosterone have experienced shrinking testicles and deep, scarring, cystic acne on their chest and back, as well as swelling of the arms and legs, fluid retention, stretch marks and psychiatric problems such as depression, anxiety and insomnia. Women who use testosterone can become permanently infertile.

Because many of the drugs are administered by injections, there is also the risk of being infected with a dirty needle.

Dr. Cayce Onks, a family and sports medicine specialist at the Medical Center, said doping controversies have been part of the Olympics since its earliest days.

This year’s headlines about the Russian Olympic team are just the latest in the saga, although with 270 Russian athletes now cleared to compete, he said it’s probably the biggest scandal to date.

These days, the incentives to take a chance on performance-enhancing drugs are huge.

“Anyone who gets a gold medal has the benefit of TV contracts, announcer gigs, commercials and all the money that comes with it. It’s not just the prestige and satisfaction of competing at that level and winning,” Onks said. “Tenths of seconds can mean the difference between a medal and no medal, so whatever they can do to get that extra tenth, they want to try.”

The Medical Minute is a weekly health news feature produced by Penn State Health Milton S. Hershey Medical Center. Articles feature the expertise of faculty physicians and staff, and are designed to offer timely, relevant health information of interest to a broad audience.

Contacts: 

Scott Gilbert

Work Phone: 

717-531-1887

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The Medical Minute: The dangerous allure of performance-enhancing drugs