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.
Tags: anthrax, antibiotic resistance, Bacillus anthracis, bacteria, cell biology, chemistry, cofactor-independent phosphoglycerate mutase, cyclic peptides, drug design, drug development, drug discovery, drug targets, drugs, glycolysis, ipglycermides, iPGM, parasite, peptide, roundworm, small molecules, Staphylococcus aureus
When Dmitry Lyumkis headed off to graduate school at The Scripps Research Institute, La Jolla, CA, he had thoughts of becoming a synthetic chemist. But he soon found his calling in a nearby lab that imaged proteins using a technique known as single-particle cryo-electron microscopy (EM). Lyumkis was amazed that the team could take a purified protein, flash-freeze it in liquid nitrogen, and then fire electrons at the protein, capturing the resulting image with a special camera. Also amazing was the sophisticated computer software that analyzed the raw 2D camera images, merging the data and reconstructing it into 3D representations of the protein.
The work was profoundly complex, but Lyumkis thrives on solving extremely difficult puzzles. He joined the Scripps lab to become a structural biologist and a few years later used single-particle cryo-EM to help determine the atomic structure of a key protein on the surface of the human immunodeficiency virus (HIV), the cause of AIDS. The protein had been considered one of the greatest challenges in structural biology and a critical target in developing an AIDS vaccine .
Now, Lyumkis has plans to take single-particle cryo-EM to a whole new level—literally. He wants to develop new methods that allow it to model the atomic structures of much smaller proteins. Right now, single-particle cryo-EM has worked with proteins as small as roughly 150 kilodaltons, a measure of a protein’s molecular weight (the approximate average mass of a protein is 53 kDa). Lyumkis plans to drop that number well below 100 kDa, noting that if his new methods work as he hopes, there should be very little, if any, lower size limit to get the technique to work. He envisions generating within a matter of days or weeks the precise structure of an average-sized protein involved in a disease, and then potentially handing it off as an atomic model for drug developers to target for more effective treatment.
Tags: 2015 NIH Director’s Early Independence Award, 3D computational analysis, atomic structure, computation, cryo-electron microscopy, cryo-EM, drug design, drug discovery, drugs, electron microscopy, HIV, human immunodeficiency virus, IKK complex, protein structure, proteins, single-particle cryo-EM, small proteins, structural biology
A little more than a decade ago, researchers began adapting a familiar commercial concept to genomics: the barcode. Instead of the black, printed stripes of the Universal Product Codes (UPCs) that we see on everything from package deliveries to clothing tags, they used short, unique snippets of DNA to label cells. These biological “barcodes” enable scientists to distinguish one cell type from another, in much the same way that a supermarket scanner recognizes different brands of cereal.
DNA barcoding has already empowered single-cell analysis, including for nerve cells in the brain. Now, in a new NIH-supported study, DNA barcoding helps in the development of a new method that could greatly streamline an increasingly complex and labor-intensive process: screening for drugs to combat cancer.
Tags: barcoded cancer cell lines, biotechnology, BRD-7880, cancer, cancer cell lines, cancer drugs, DNA barcode, drug discovery, drug screening, genomics, mechanism of action, oncology, Precision Medicine Initiative, PRISM, Profiling Relative Inhibition Simultaneously in Mixtures, single cell analysis
In the quest to find faster, better ways of mapping the structure of proteins and other key biological molecules, a growing number of researchers are turning to an innovative method that pushes the idea of a freeze frame to a whole new level: cryo-electron microscopy (cryo-EM). The technique, which involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera, has advanced dramatically since its inception thanks to the efforts of many creative minds. In fact, cryo-EM has improved so much that its mapping performance now rivals that of X-ray crystallography , the long-time workhorse of drug developers and structural biologists.
To get an idea of just how far cryo-EM has come over the last decade, take a look at the composite image above, which shows a bacterial enzyme (beta-galactosidase) bound to a drug-like molecule (phenylethyl beta-D-thiogalactopyranoside). To the left, you see a blob-like area generated by cryo-EM methods that would have been considered state-of-the-art just a few years ago. To the right, there’s an exquisitely detailed structure, which was produced at more than 10-times greater resolution using the latest advances in cryo-EM. In fact, today’s cryo-EM is so powerful that researchers can almost make out individual atoms! Very impressive, and just one of the many reasons why the journal Nature Methods recently named cryo-EM its “Method of the Year” for 2015 .
Tags: 3D imaging, Alzheimer’s disease, beta-galactosidase, computational methods, cryo, cryo-electron microscopy, cryo-EM, drug discovery, electron microscopy, electrons, HIV, imaging, imaging method, Method of the Year, microscopy, molecules, NMR, nuclear magnetic resonance spectroscopy, phenylethyl beta-D-thiogalactopyranoside, protein maps, protein structures, small molecules, x-ray crystallography