Science Concentrates CHEMICAL SENSING TOXICOLOGY
Detecting food allergens on the go
▸ How poison dart frogs avoid poisoning themselves
A single amino acid swap keeps golden poison dart frogs safe from their own toxin. 2 mg in adults—to kill more than 20,000 mice, yet their voltage-gated sodium channel membrane protein is immune to its paralytic effects. Sho-Ya Wang and Ging Kuo Wang of the University at Albany now report that a single amino acid swap can render sodium channels almost completely resistant to batrachotoxin. The researchers built off a study published last year by another research team that identified five amino acid substitutions differentiating poison dart frog and rat sodium channels. In the new study, scientists tested whether creating the five frog substitutions in the rat sodium channel, individually and in combination, conferred batrachotoxin resistance. Monitoring cells engineered to produce either normal or modified sodium channels revealed that replacing just one amino acid—asparagine with threonine at HO3SO
HO3SO
O
HO HO
NH HO3S
HO2C O HO
O
O
O HO C 2
NH HO3S
O
OH O O HO
HO3SO
position 1,584—conferred “exceptional” batrachotoxin resistance (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1707873114). Sodium channels with substitutions at the other four locations remained sensitive to the toxin. Sho-Ya Wang says gaining a better understanding of how batrachotoxin interacts with sodium channels may help improve the design of therapeutic drugs that target the same region of the protein.—EMMA HIOLSKI
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C&EN | CEN.ACS.ORG | SEPTEMBER 11, 2017
killed people. A synthetic heparin called fondaparinux is safer and homogeneous. But people taking heparin sometimes experience uncontrolled bleeding, and although a drug called protamine can reverse the anticoagulant activity of unfractionated heparin, it does so incompletely with low-molecular-weight heparin and doesn’t reverse fondaparinux activity at all. Robert J. Linhardt of Rensselaer Polytechnic Institute, Jian Liu of the University of North Carolina, Chapel Hill, and coworkers re-
▸ Synthetic heparin could improve bloodthinning treatments A new synthetic version of the sulfated polysaccharide heparin that could be safer or have more-reversible activity than currently approved versions of the
HO3SO
O
OH HO3S
DRUG DEVELOPMENT
HO3SO
O HO C 2
NH HO3S
O
HO3SO
OH O O HO
HO3SO
HO3SO
O HO C 2
NH HO3S
O
HO3SO
O HO C 2
OH O O HO
NH HO3S
O
HO3SO
NO2
O
OH O O HO
NH HO3S
HO2C O HO
O
O
OH
12-mer-1
anticoagulant has been produced in quantities that begin to approach those needed for commercialization. Three types of heparins are currently approved as blood thinners to treat clotting disorders and prevent clotting in people undergoing kidney dialysis and surgery. Unfractionated heparin and low-molecular-weight heparin, derived from pig intestines, are mixtures with batch-to-batch inconsistencies, and contaminated batches have at times
cently used chemoenzymatic synthesis to make a synthetic heparin that is less prone to contamination, more consistent, and more amenable to protamine reversal than other heparins are. But they could produce only milligram amounts. Now, a group led by Linhardt, Liu, and UNC’s Rafal Pawlinski has added a sulfate that makes the heparin easier to synthesize, boosted the activity of two key enzymes, and found a way to produce cofactors in higher yield. The
C R E D I T: ACS N A NO ( D E T ECTO R ) ; M IC H A L . R I ES E R / WI KI MED I A CO MMO N S (F RO GS )
Doctors estimate that each year more than 200,000 people in the U.S. visit hospital iEAT consists of a portable antigen extraction kit and a emergency rooms because of food allergies. key-chain detector. This number includes an estimated 90,000 cases of life-threatening anaphylaxis. The main approach doctors recommend when it comes to food allergies is simply to avoid those foods. But that can be difficult when eating at restaurants or when traveling to countries that have less-stringent food allergen labeling laws. Researchers led by Massachusetts General Hospital’s Hakho Lee and Ralph Weissleder have now developed a prototype point-of-use allergen detection system that picks up traces of peanuts, hazelnuts, wheat, milk, and egg whites in less than 10 minutes (ACS Nano 2017, DOI: 10.1021/acsnano.7b04318). The system, dubbed iEAT, requires two steps: antigen extraction followed by detection. Antigens in the food are captured with antibody-containing magnetic beads, which are subsequently labeled with other antibodies conjugated to the oxidizing agent horseradish peroxidase. A sheathed magnet collects the magnetic beads, which are then placed on the detector, where they undergo an electrochemical reaction. The major innovation, Lee notes, is the detector that fits on a key chain, which can differentiate up to eight allergens, connect to smartphones via Bluetooth, and charge wirelessly. Each disposable antigen extraction system costs about $4.00, and the detector costs $40.—BETHANY HALFORD
Scientists have wondered how golden poison dart frogs resist succumbing to the high doses of toxin they store in their skin. Certain species of Phyllobates frogs are loaded with enough batrachotoxin—up to
redesigned heparin, called 12-mer-1, can be produced in gram amounts and retains protamine reversibility. The researchers tested it successfully in mice and monkeys (Sci. Transl. Med. 2017, DOI: 10.1126/scitranslmed.aan5954).—STU BORMAN
SYNTHESIS
▸ Cross metathesis cleaves and restitches single bonds Chemists have developed an array of chemical tools that rely on reactive carbon-carbon π bonds or on polar bonds in which charge is unevenly shared between the atoms to drive the formation of new carbon-carbon bonds. Yet methods that act on challenging, nonpolar carbon-carbon bonds are few. Researchers led by Masa-
O R
R2 + R1 Si
R2
R1 Palladium catalyst
Si R
R = various groups; R1, R2 = alkyl or phenyl
O
hiro Murakami of Kyoto University have expanded the synthetic options by demonstrating the efficient exchange of two low-polarity σ bonds in a cross-metathesistype reaction catalyzed by a palladium isocyanide complex (J. Am. Chem. Soc. 2017 DOI: 10.1021/jacs.7b07667). The method regioselectively opens the four-membered rings of benzocyclobutenone and silacyclobutane and exchanges C(aryl)–C(carbonyl) and C(sp3)–Si bonds to create C(aryl)–Si and C(carbonyl)–C(sp3) bonds and form an eight-membered-ring product. “The work provides a striking demonstration of how metallacycles derived from C–C bond activation can be used to access challenging medium-ring systems,” comments the University of Bristol’s John Bower. “These results suggest that a range of σ-bond-metathesis-based cycloadditions might be achievable by metal-catalyzed union of strained rings.”—TIEN NGUYEN
C R E D I T: S CI . T RAN S L. M ED.
MASS SPECTROMETRY
▸ Nondestructive surgical mass spec During cancer surgery, surgeons often must wait for pathologists to analyze a removed tissue sample to confirm they’ve gotten all
INORGANIC CHEMISTRY
Cagey silicophosphates Silicophosphates are network compounds with Si–O–P linkages that form highly porous materials with enormous surface area. These materials, known as xerogels, are of interest for their possible use in making ion-conducting films for sensors, catalyst supports, biocompatible O materials such as dental cement, and storage maR terials for confining nuclear waste. But because O P O R silicophosphates are made from moisture-sensiSi R Si O R tive starting materials and tend to be moisture Si R O O sensitive themselves, their reproducible O synthesis has been a challenge and only a O RR R P P O few examples are known. Jiri Pinkas and O Si O O R colleagues at Masaryk University in the O Si O P O Czech Republic have been perfecting Si R condensation reactions of acetoxysilanes O R R and trimethylsilyl phosphates under anR = phenyl hydrous conditions to make molecular Silicophosphate cage silicophosphates. In its latest work, the Pinkas group has built an adamantane-like cage molecule that has not been seen before (Inorg. Chem. 2017, DOI: 10.1021/acs.inorgchem.7b01572). When the researchers treated the silicophosphate with the Lewis acid B(C6F5)3, they found that boron coordinates to the phosphate groups to form two new compounds. One compound has three borane-phosphate pairs, but one of its P=O groups remains free and is inverted to the center of the cage, giving rise to threefold symmetry—the molecule is chiral with two enantiomers. The second compound undergoes reorganization of the Si–O–P linkages to form yet another new but smaller silicophosphate cage. The researchers anticipate that ongoing study of the synthesis, structure, and bonding of the silicophosphates will lead to additional design ideas for functional materials.—STEVE RITTER
the cancer. Researchers have previously shown that analyzing tissue with mass spectrometry during surgery can help speed this process. But those surgical mass spec approaches rely on methods that often damage the tissue or are suitable only for analyzing removed samples. Livia S. Eberlin of the University The MasSpec Pen has three conduits, two of which of Texas, Austin, and deliver water droplets and low-pressure gas and one of coworkers have now which transports the water droplet to an attached mass come up with a biospectrometer. The extraction process takes three seconds. compatible device that used the device to sample 253 tissue pieces uses discrete water droplets to nondestrucfrom a variety of cancers, finding that the tively obtain molecular profiles of cancer mass spectra allow them to distinguish tissue (Sci. Transl. Med. 2017, DOI: 10.1126/ between cancer tissue and normal tissue, scitranslmed.aan3968). The handheld deincluding in samples containing both types vice delivers a water droplet to the tissue of tissue. In addition, the researchers used surface, where it gently extracts metabothe device to diagnose cancer in live mice lites, lipids, and proteins. Afterward, a plasduring surgery without damaging tissue or tic tube carries the water droplet to an atstressing the animals.—CELIA ARNAUD tached mass spectrometer. The researchers SEPTEMBER 11, 2017 | CEN.ACS.ORG | C&EN
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