Science Concentrates DRUG DISCOVERY
▸ Alzheimer’s drug candidate shows promise
NH F
N
H N
HN
CH3 N S O O
O
F Verubecestat
from trials because of off-target side effects such as liver toxicity. The BACE1 inhibitor verubecestat (MK-8931), currently being evaluated in two Phase III trials scheduled for completion in 2017 and 2019, seems to be more benign. Matthew E. Kennedy, Andrew W. Stamford, Eric M. Parker, Mark S. Forman, and coworkers at Merck report that in Phase I studies it showed relatively mild side effects, similar to those of placebos (Sci. Transl. Med. 2016, DOI: 10.1126/ scitranslmed.aad9704). Four other BACE1 inhibitors are in clinical trials, but how their efficacy and safety compare with verubecestat’s isn’t yet clear. Riqiang Yan of Cleveland Clinic Foundation, a codiscoverer of BACE1, comments that verubecestat could offer hope to Alzheimer’s patients if its side-effect profile remains favorable when administered long-term.—STU BORMAN
DRUG DISCOVERY
▸ Small molecule stalls PCSK9 translation Last week, Pfizer announced it would stop work on bococizumab, a monoclonal antibody designed to inhibit the cholesterol regulator proprotein convertase subtilisin/
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C&EN | CEN.ACS.ORG | NOVEMBER 7, 2016
This pristine 10,000-yearold deer antler from the Star Carr site was likely a headdress used by shamans.
ART & ARTIFACTS
Ancient artifacts dissolved by soil’s sulfuric acid For millennia, the wet boggy conditions at the Star Carr archeological site in Eastern England kept a cornucopia of 10,000-year-old, Stone Age wood and bone objects, including 22 red deer antler headdresses used in shaman rituals, in pristine condition. But in the early 2000s, the land was drained for agriculture, dropping the water table and drying out the archeological site. Since then, archeologists have been alarmed to find that recently unearthed objects at the site are degrading rapidly. Scientists believe oxygen is now reaching sulfur-rich sediments lying below the artifacts. Consequently, sulfides are being oxidized to sulfuric acid, causing acidification of soil near the artifacts to a pH level of 2. A team led by the University of York’s Kirsty Penkman created a lab model of the site to figure out how this geochemistry is affecting the artifacts (Proc. Natl. Acad. Sci. USA 2016, DOI: 10.1073/pnas.1609222113). The team found that these changes in soil geochemistry have accelerated the breakdown of hydroxyapatite in bone artifacts and lignin in wood artifacts. “Our research demands a reassessment of the assumption that sites such as Star Carr should be preserved in situ,” the study’s authors note.—SARAH EVERTS
kexin type 9 (PCSK9) because few proteins,” the researchers of weak data and a changing note. The compound lowered N Cl cholesterol levels in rats. PCSK9 market for lipid-lowering agents N O prevents the receptors that re(see page 15). The news came HN just one week after Pfizer scimove low-density lipoprotein entists, led by Robert Dullea, cholesterol—also known as reported a small molecule that LDL or “bad” cholesterol—from can shut down translation of doing their job. Two monocloN N PCSK9 (bioRxiv 2016, DOI: N nal antibody drugs that block 10.1101/083097). The work, PCSK9 have been approved to N which appeared on a preprint lower LDL cholesterol in certain server and has not yet been peer PF-06446846 patients, but to date, no small reviewed, was done in collaboramolecule aimed at lowering tion with University of California, BerkePCSK9 has been approved. This study, the ley, researchers led by Jamie Cate. The authors write, “reveals a previously unexsmall molecule, known as PF-06446846, pected tunability of the human ribosome, appears to cause the ribosome to stall which allows small molecules to specifiwhen synthesizing PCSK9. “PF-06446846 cally block translation of individual tranis exceptionally specific, affecting very scripts.”—BETHANY HALFORD
CREDIT: PROC. NATL. ACAD. SCI. USA /SCARBOROUGH MUSEUMS TRUST
In an early Phase I study, an Alzheimer’s drug candidate showed reduced side effects compared with similar drugs that have failed clinical trials. The agents inhibit BACE1, an enzyme whose activity leads to β-amyloid peptide (Aβ) production. The idea is that inhibiting Aβ formation to reduce growth of Aβ-based plaques in the brains of Alzheimer’s patients may be therapeutic, although it isn’t yet clear how early in the disease process such an intervention would need to be employed to be effective. Several BACE1 inhibitors were withdrawn
BIOCHEMISTRY
▸ Fetal genome sequenced at five weeks Just five weeks into gestation, a fetus can have its DNA collected during its mother’s routine Pap smear and accurately genotyped, according to a study (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed. aah4661). The development holds promise for early genetic testing for thousands of birth defects. To obtain such information currently, pregnant women must undergo invasive and risky procedures such as chorionic villus sampling (CVS), a tissue analysis technique, at around 10–12 weeks’ gestation or amniocentesis at 16–18 weeks. Progress has also been made in the development of tests that detect snippets of fetal DNA in a mother’s blood. However, it can be difficult to generate an accurate picture of a fetal genome from these methods. Now, a team led by Chandni V. Jain, Sascha Drewlo, and D. Randall Armant of Wayne State University School of Medicine isolated placental cells known as trophoblasts from cervical canal swabs of 20 pregnant women at five to 19 weeks’ gestation. Trophoblasts carry fetal DNA, which the team was able to isolate and distinguish from the mothers’ DNA. They also showed that the fetal DNA quality is on par with DNA obtained through CVS or amniocentesis. The authors say tests can be developed for this source of fetal DNA that could identify single gene mutations, such as those responsible for some metabolic syndromes.—ELIZABETH WILSON
BIOTECHNOLOGY
CREDIT: NAT. METHODS
▸ Protein evolution’s CRISPR way forward Directed evolution is a powerful tool that allows researchers to simulate natural selection. Many such experiments place human genes into bacteria or yeast. Researchers then randomly mutate those genes in hopes of improving a protein’s function. But Gaelen T. Hess and colleagues of Stanford University wanted to give directed evolution experiments more guidance and do the entire process in cultured human cells. So they turned to CRISPR gene editing for
CATALYSIS
Onward to simpler C–H functionalizations Selective C–H activation and functionalization has emerged as an integral strategy for organic synthesis. Chemists have already developed an abundant set of methods, and many researchers are now turning to finding ways of simplifying those strategies. In one of the latest examples, a team led by Kenichiro Itami of Nagoya University and Djamaladdin G. Musaev of Emory University has used a computational-experimental approach to create a predictive regioselective reaction for C–H imidation of aromatic compounds (Chem. Sci. NFSI, CuBr, bipyridine ligand
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. CuII
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Charge predicts selectivity
N
SO2C6H5
N N
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Active catalyst 2016, DOI: 10.1039/c6sc04145k). One hurdle for C–H functionalization has been that it’s a two-electron oxidation process, but inexpensive first-row transition metals used as catalysts typically are capable of one-electron redox activity. The way around this problem is to use two concurrent one-electron oxidations, which typically requires two catalysts. Itami, Musaev, and their team have found that treating copper bromide and a bipyridine ligand with the commercially available oxidizing reagent N-fluorobenzenesulfonimide (NFSI) leads to a new class of dinuclear copper catalysts in which the two Cu(II) centers work collectively to guide NFSI-promoted aromatic C–H imidation. As a bonus to the process, the researchers developed a way to calculate the charge on carbon atoms in aromatic molecules to predict which C–H bond is favored for imidation (shown above).—STEVE RITTER
inspiration and developed a new method called CRISPR-X, which allows scientists to study effects of random mutations in small stretches of DNA (Nat. Methods 2016, DOI: 10.1038/nmeth.4038). First, a
Fused MS2 and AID proteins are recruited to the dCas9 site where AID induces DNA mutations (stars).
catalytically dead version of the protein Cas9, called dCas9, is directed to a location along the genome matching its guide RNA. To induce mutations in the region, the team appended two hairpin loops that bind a viral protein called MS2 to the guide RNA. Finally, the MS2 protein, which the researchers fused to a mutation-inducing enzyme called AID, is expressed in the cell. There, it is recruited to the dCas9, enabling hypermutation at that site. “This is much more targeted than what people have done before,” Hess says. He foresees researchers using the system to mutate two different protein binding sites to study protein-protein interactions and to study mammalian regulatory elements that turn genes on and off.—RYAN CROSS NOVEMBER 7, 2016 | CEN.ACS.ORG | C&EN
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