NEWS OF TH E WEEK
DRUG ASSEMBLY ON-SITE DRUG DELIVERY: Click reaction
links small molecules to form larger potential drug inside cells
I
ANGEW. CHEM.
When a number of derivatized smallmolecule inhibitors bind to an RNA repeat sequence in cells, their alkyne and azide groups react with one another, producing potent oligomers.
F A MULTICOMPONENT bioactive agent is too big to
slip into cells, it would be nice to get its components into cells first and then combine them on-site. That’s
what Matthew D. Disney, Suzanne G. Rzuczek, and HaJeung Park at Scripps Research Institute Florida did with a potential myotonic dystrophy type 2 (DM2) treatment (Angew. Chem. 2014, DOI: 10.1002/ange.201406465). DM2 is a rare condition characterized by muscle pain and weakness. It’s caused by a genetic defect that generates toxic RNA with a four-nucleotide repeat pattern. Disney and coworkers earlier discovered a small molecule that improves DM2 symptoms by inhibiting the re-
JAPAN OFFERS EBOLA TRIAL DRUG PHARMACEUTICALS: Fujifilm influenza treatment is available if health officials want it
T
O F
N N H
NH2 O
Favipiravir
HE JAPANESE GOVERNMENT said last week
that it is prepared to make an influenza drug that is not approved for the treatment of Ebola available to West African countries hard-hit by the deadly virus. “We have been informed that there are inquiries from those countries about the medicine developed by a Japanese company that may be effective in treating the virus,” Yoshihide Suga, chief cabinet secretary, said at a press conference last week. If requested to do so by the World Health Organization, “we will provide it in cooperation with the company,” Suga said. The drug, favipiravir, brand-named Avigan, is manufactured by Fujifilm subsidiary Toyama Chemical and was approved in Japan as an influenza treatment earlier this year. Avigan, a polymerase inhibitor, stifles viral gene replication within infected cells to prevent the spread CEN.ACS.ORG
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peat sequence in cells. They wanted to boost its efficacy by linking a number of the molecules together. But the combination agent’s size limits its ability to enter cells. The team therefore synthesized a version of the small molecule derivatized with azide and alkyne groups. The compound binds to the toxic RNA repeat sequence such that the azide and alkyne groups are close enough to react by Huisgen 1,3-dipolar cycloaddition, a form of click chemistry. The reaction combines the small-molecule units into oligomers that are more powerful inhibitors of RNA dysfunction than the individual molecules alone. The reaction is bioorthogonal—it doesn’t disturb normal biological processes. It’s also selective in that it only occurs in cells containing the DM2 repeat sequence, which is required to catalyze it. The strategy also might lead to oligomer therapeutics for Lou Gehrig’s disease (amyotrophic lateral sclerosis), which is caused by a similar repeat defect. “Bioorthogonal chemistry has mostly been used for the ex vivo modification of biomolecules or for detecting the presence of molecules in living systems,” comments M. G. Finn of Georgia Tech, an expert in the field. “It has always been a dream of this community to assemble functional molecules at the site of action. Disney and coworkers have done a delightful job of this. They chose the target and beautifully designed the approach for easy engineering of selectivity and efficacy. The functional outcome is undeniable and remarkably useful.”—STU BORMAN
of the virus to uninfected cells. As a treatment for influenza, the drug is an alternative to neuraminidase inhibitors such as Tamiflu and Relenza, which act by inhibiting the release of viral particles from infected cells. Although Avigan has not been tried on Ebola patients, a Fujifilm spokeswoman says the company is aware of tests performed by independent researchers that show it reduces Ebola infection in mice. The company, she says, has sufficient supplies of favipiravir for more than 20,000 people and has developed a system for continuous production of the drug. Avigan joins a growing roster of potential treatments for the disease, which has killed nearly 1,500 people in the current outbreak. One drug, ZMapp, an antibody mixture developed by Mapp Biopharmaceutical, seemed effective for two American aid workers, who were able to leave an Atlanta hospital late last month after being infected in Africa. However, a doctor in Liberia died after being treated with ZMapp. Other drugs in development to treat the disease include an siRNA compound from Tekmira Pharmaceuticals and an antisense drug from Sarepta Therapeutics. And the National Institute of Allergy & Infectious Diseases will begin human safety tests this week on a GlaxoSmithKline vaccine in development for the treatment of Ebola. In parallel, a British-based consortium will test the vaccine in volunteers in the U.K. and Africa.—RICK MULLIN
SEPTEMBER 1, 2014
