Fighting Parasitic Infections: Promise in Cyclic Peptides

Cyclic peptide bound to iPGM

Caption: Cyclic peptide (middle) binds to iPGM (blue).
Credit: National Center for Advancing Translational Sciences, NIH

When you think of the causes of infectious diseases, what first comes to mind are probably viruses and bacteria. But parasites are another important source of devastating infection, especially in the developing world. Now, NIH researchers and their collaborators have discovered a new kind of treatment that holds promise for fighting parasitic roundworms. A bonus of this result is that this same treatment might work also for certain deadly kinds of bacteria.

The researchers identified the potential new  therapeutic after testing more than a trillion small protein fragments, called cyclic peptides, to find one that could disable a vital enzyme in the disease-causing organisms, but leave similar enzymes in humans unscathed. Not only does this discovery raise hope for better treatments for many parasitic and bacterial diseases, it highlights the value of screening peptides in the search for ways to treat conditions that do not respond well—or have stopped responding—to more traditional chemical drug compounds.

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Snapshots of Life: Virus Hunting with Carbon Nanotubes

H5N2 trapped in carbon nanotubes

Credit: Penn State University

The purple pods that you see in this scanning electron micrograph are the H5N2 avian flu virus, a costly threat to the poultry and egg industry and, in very rare instances, a health risk for humans. However, these particular pods are unlikely to infect anything because they are trapped in a gray mesh of carbon nanotubes. Made by linking carbon atoms into a cylindrical pattern, such nanotubes are about 10,000 times smaller than width of a human hair.

The nanotubes above have been carefully aligned on a special type of silicon chip called a carbon-nanotube size-tunable-enrichment-microdevice (CNT-STEM). As described recently in Science Advances, this ultrasensitive device is designed to capture viruses rapidly based on their size, not their molecular characteristics [1]. This unique feature enables researchers to detect completely unknown viruses, even when they are present in extremely low numbers. In proof-of-principle studies, CNT-STEM made it possible to collect and detect viruses in a sample at concentrations 100 times lower than with other methods, suggesting the device and its new approach will be helpful in the ongoing hunt for new and emerging viruses, including those that infect people.

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Creative Minds: Can Diseased Cells Help to Make Their Own Drugs?

Matthew Disney

Matthew Disney

Matthew Disney grew up in a large family in Baltimore in the 1980s. While his mother worked nights, Disney and his younger brother often tagged along with their father in these pre-Internet days on calls to fix the microfilm machines used to view important records at hospitals, banks, and other places of business. Watching his father take apart the machines made Disney want to work with his hands one day. Seeing his father work tirelessly for the sake of his family also made him want to help others.

Disney found a profession that satisfied both requirements when he fell in love with chemistry as an undergraduate at the University of Maryland, College Park. Now a chemistry professor at The Scripps Research Institute, Jupiter, FL, Disney is applying his hands and brains to develop a treatment strategy that aims to control the progression of a long list of devastating disorders that includes Huntington’s disease, amyotrophic lateral sclerosis (ALS), and various forms of muscular dystrophy.

The 30 or so health conditions on Disney’s list have something in common. They are caused by genetic glitches in which repetitive DNA letters (CAGCAGCAG, for example) in transcribed regions of the genome cause some of the body’s cells and tissues to produce unwieldy messenger RNA molecules that interfere with normal cellular activities, either by binding other intracellular components or serving as templates for the production of toxic proteins.

The diseases on Disney’s list also have often been considered “undruggable,” in part because the compounds capable of disabling the lengthy, disease-causing RNA molecules are generally too large to cross cell membranes. Disney has found an ingenious way around that problem [1]. Instead of delivering the finished drug, he delivers smaller building blocks. He then uses the cell and its own machinery, including the very aberrant RNA molecules he aims to target, as his drug factory to produce those larger compounds.

Disney has received an NIH Director’s 2015 Pioneer Award to develop this innovative drug-delivery strategy further. He will apply his investigational approach initially to treat a common form of muscular dystrophy, first using human cells in culture and then in animal models. Once he gets that working well, he’ll move on to other conditions including ALS.

What’s appealing about Disney’s approach is that it makes it possible to treat disease-affected cells without affecting healthy cells. That’s because his drugs can only be assembled into their active forms in cells after they are templated by those aberrant RNA molecules.

Interestingly, Disney never intended to study human diseases. His lab was set up to study the structure and function of RNA molecules and their interactions with other small molecules. In the process, he stumbled across a small molecule that targets an RNA implicated in a rare form of muscular dystrophy. His niece also has a rare incurable disease, and Disney saw a chance to make a difference for others like her. It’s a healthy reminder that the pursuit of basic scientific questions often can lead to new and unexpectedly important medical discoveries that have the potential to touch the lives of many.

Reference:

[1] A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Rzuczek SG, Park H, Disney MD. Angew Chem Int Ed Engl. 2014 Oct 6;53(41):10956-10959.

Links:

Disney Lab (The Scripps Research Institute, Jupiter, FL)

Disney NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke

Summer Reading Suggestions from Scientists: Karl Deisseroth

Summer Reading

Non-Science Selection:

Romila Thapar, History of Early India from Origins to AD 1300. Last January, I was traveling in several cities in India and asked my hosts far too many questions about early Indian history. In the end, one of them (Narasimhan Ram, publisher of the newspaper The Hindu) gave me a number of books, including this text written by a leading Indian historian Romila Thapar. Beyond Thapar’s erudite and level-headed historical scholarship, she did not refrain from fascinating speculation. For example, she speculates on the strongest initial threads of political power, beyond conquest, arising in ritual and culture—much discussed, but here tied to specific archaeological/prehistorical data. Although the specifics in the book itself are on the movement of peoples, conflicts, and cultural shifts that defined the early demographics, politics, and linguistic structures of the Indian subcontinent, the big ideas map readily onto issues that are pressing in the modern world, regarding migration and the sources of cultural authority. The themes of human history that we are reliving today are so vivid, that every few pages a sentence or paragraph would leap out from the page, and I found I had to stop and put down the book for quite some time before continuing—unusual (at least for me) in reading a text of this kind.

Science Selection:

Primo Levi, The Periodic Table. Every few years, rereading this brief masterpiece published by such a gifted writer, chemist, and direct witness to the extremes of the human experience is rewarding in a new way. The vignettes within this volume, at each reading, seem to provide a fresh perspective on the human condition, and remain relevant despite (or perhaps because of) the rapidity of change in this condition. Among its more explicitly scientific themes, the special beauty of chemistry shines forth throughout (with particular resonance for me, as with many biologists, since my own first steps toward science were from a foundation of organic and synthetic chemistry, and still to this day all of my approaches to neuroscience and psychiatry remain rooted in chemistry). The book is also autobiographical and historical, infused with Levi’s personal perspective on the horrific sociology of rising totalitarianism; tragically, this perspective may be increasingly relevant today, and historians, linguists, social scientists, anthropologists, and biologists all find meaning here. The book is composed of many independent short chapters, each titled by an element—and each reader seems to end up with a different list of favorites (the book includes purely fictional components, and, if you only have time for one of the more imaginative chapters to form an opinion of those, you can start with my personal favorite among the historical fantasies, “Lead”).

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Karl Deisseroth

Karl Deisseroth
Credit: Alison Yin/ AP Images for HHMI

Karl Deisseroth, MD, PhD is the D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University; a foreign adjunct professor at Karolinska Institutet, Stockholm; a Howard Hughes Medical Institute investigator; and a visiting professor at Keio University, Tokyo. Dr. Deisseroth has developed a number of innovative research tools to study the brain, human behavior, and mental illness. Since 2014, Dr. Deisseroth has received two Dickson Prizes, the Albany Prize in Medicine and Biomedical Research, the Lurie Prize in Biomedical Sciences, and the Breakthrough Prize in Life Science.

Creative Minds: A New Chemistry for Aging Research?

Tony Wyss-Coray

Tony Wyss-Coray / Credit: Stanford School of Medicine

Basic scientists have long studied aging by looking inside of cells. While this research has produced many important leads, they are now starting to look outside the cell for the wealth of biochemical clues contained in the bloodstream.

To introduce you to this exciting frontier in aging research, this blog highlighted a while back the work of Tony Wyss-Coray at Stanford School of Medicine, Palo Alto, CA. He and a colleague had just received a 2013 NIH Director’s Transformative Research Award to explore the effects of exercise on the brains of mice. Their work, in fact, produced one of Science Magazine’s Breakthrough Discoveries of 2014. Their team showed that by fusing the circulatory systems of old and young mice to create a shared blood supply, the young blood triggered new muscle and neural connections in the older mice, while also improving their memories.

As fascinating as this theoretical Fountain of Youth was, Wyss-Coray recognized a critical limitation. He had no way of knowing how factors secreted by the young mouse could actually cross the blood-brain barrier and rejuvenate neurons. To solve this unknown, Wyss-Coray recently received a 2015 NIH Director’s Pioneer Award to build a potentially game-changing tool to track the aging process in mice.

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