Science Concentrates DRUG DEVELOPMENT
‘Molecular prosthetic’ moves iron Small molecule stands in for missing iron transporters in cells and animals resents a possible new type of therapeutic. Many small-molecule drugs treat disease by shutting down unwanted protein activity. “But if a patient is sick not because of too much protein function but instead because of a deficiency, then the classic O paradigm of pharmacology falls OH apart,” Burke says. “There is no target to inhibit.” For example, some rare cases of anemia are caused by the lack of iron transporters responsible for moving iron ions across lipid membranes and into, out of, or within cells. Without these proteins’ activity, the ions pool on one side of a membrane, unable to eventually reach cellular compartments where hemoglobin is built. Burke, along with Jonghan Kim of Northeastern University, Marianne Wessling-Resnick and Barry H. Paw of Harvard University, and others, Hemoglobin in these zebrafish is stained brown found a natural product, hinokitiol, (arrow, left). Fish engineered to lack the iron that can rescue stranded iron. The transporter mitoferrin had lower levels of researchers think three hinokitiol hemoglobin (center). But adding hinokitiol to molecules bind a single iron ion, the engineered fish’s tank returned levels to forming a greasy sphere around the normal (right). charged species that can then move through hydrophobic membranes. 2017, DOI: 10.1126/science.aah3862). MarIn experiments in cells and animals, tin D. Burke of the University of Illinois, the team demonstrated that hinokitiol Urbana-Champaign, one of the study’s could mimic the activity of three differlead scientists, thinks the compound repent iron transporters. For example, ze-
CREDIT: SCIENCE (ZEBRAFISH); WIKIMEDIA COMMONS (PROTEIN)
A prosthetic hand or leg can’t do everything that a lost appendage once did. But these devices often restore enough function to help people regain some quality of life that loss of a limb takes away. Small molecules might similarly help people with diseases caused by absent or defective proteins, according to a new study. Researchers report a “molecular prosthetic” that can move iron to where it’s needed in cells and animals that lack proteins to transport the metal (Science
Three molecules of hinokitiol (structure below) bind to a single iron ion. brafish genetically engineered to lack the transporter mitoferrin had low levels of hemoglobin in their blood cells. The scientists could return those levels to normal by adding hinokitiol to the fish tank. Developing a molecule that can move iron to where it’s needed in cells is novel and potentially important, says Nancy C. Andrews, dean of Duke University School of Medicine. Such a molecule, she says, could help treat anemias involving iron imbalances seen in diseases such as cancer and rheumatoid arthritis. But, Andrews says, the scientists first need to test the efficacy and toxicity of hinokitiol in animal models of these conditions. Burke says the team plans to further examine hinokitiol’s therapeutic potential, but he thinks the lesson of the study’s findings is “imperfection is enough”: Although transporters are much larger and more complex than hinokitiol, the molecule could mimic enough of the proteins’ activity to restore cells’ normal physiology. Burke’s lab hopes to use this concept to find molecular prosthetics for other conditions involving missing proteins.—MICHAEL TORRICE
SYNTHETIC BIOLOGY
Ancient protein protects modern bacteria Researchers have resurrected a 2.5 billion-year-old protein, engineered its gene sequence into modern Escherichia coli, and observed that the modified bacteria could avoid harm from invading viruses. The protein hails from the Precambrian era and is the ancient form of thioredoxin, which plays an important role in all organisms studied to date: It shuttles electrons around a cell so that chemical reactions can occur.
Both then and now, the bacteriophage T7 virus successfully infects host E. coli by hijacking the bacterium’s thioredoxin. Although the overall architecture of ancient and modern thioredoxin is the same, the proteins’ amino acid sequences are only about 70% similar. The 30% difference is
Thioredoxin shuttles electrons around a cell and can be co-opted during some viral infections.
big enough to protect ancient thioredoxin engineered into E. coli (J. Cell Rep. 2017, DOI: 10.1016/j.celrep.2017.04.037). The research team, led by Jose M. Sanchez-Ruiz at the University of Granada, argues that the strategy of inserting genes for ancient proteins into modern organisms could be useful in both synthetic biology and crop protection. For example, agricultural plants could be engineered to produce ancient proteins so that pathogens cannot hijack the crops, and thereby our food supply.—SARAH EVERTS MAY 15, 2017 | CEN.ACS.ORG | C&EN
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