NEWS OF THE W EEK
ANTI-HIV DRUG SIDESTEPS RESISTANCE
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TMC278
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DRUG DISCOVERY: Inhibitor modifies its shape to accommodate mutations
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UMAN IMMUNODEFICIENCY virus is usually pretty good at mutating, thereby developing resistance to antiretroviral drugs. Agents targeting the virus’s reverse transcriptase enzyme sometimes lose their efficacy when the enzyme mutates, but the inhibitor TMC278 (rilpivirine) tends to remain effective. Researchers have now obtained crystal structures that show that the drug shifts its shape, enabling it to hold on to mutated versions of the enzyme, an ability that might be incorporated into the design of other drugs. TMC278 “is a highly promising compound” that has shown efficacy against a broad range of drug-resistant HIV variants, says virologist John M. Coffin of Tufts University, who did not participate in the new study. The compound is entering Phase III clinical trials sponsored by Tibotec Pharmaceuticals.
Watch TMC278’s shape shift as HIV mutates at C&EN Online, www.cen-online.org.
TOXICOLOGY JOURNAL ENHANCED PUBLISHING: Chemical Research in
Toxicology now carries news and a more international flavor
CHEM. RES. TOXICOL.
Chemical Research in Toxicology is introducing new features beginning with January’s 20th-anniversary issue.
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HE AMERICAN Chemical Society is expanding the features offered by its Chemical Research in Toxicology journal. Making its debut with the 20th-anniversary January issue, the new design was “developed specifically to engage a broader and more international audience,” says Evelyn Jabri, senior acquisitions editor for ACS journals. “I’m really excited about the expanded vision for the journal and I’m extremely grateful to ACS,” says Lawrence J. Marnett, editor of Chemical Research in Toxicology. The society’s investment in the project “shows a lot of confidence in the direction of the journal,” adds Marnett, who is a professor of cancer research and of biochemistry, chemistry, and pharmacology at Vanderbilt University. The monthly journal covers structural, mechanistic, and technological advances in research related to the toxic effects of chemical agents. WWW.C E N- ONLI NE .ORG
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To learn why TMC278 inhibits HIV reverse transcriptase so persistently, a research team has obtained high-resolution crystal structures of the native enzyme and two key drug-resistant mutants, each bound to TMC278. The structures show that the inhibitor’s compactness and flexibility enable it to adjust its conformation to accommodate mutational changes in the enzyme binding pocket (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0711209105). The work was carried out by professor of chemistry and chemical biology Eddy Arnold of Rutgers University, whose group helped discover TMC278; Aaron J. Shatkin, professor and director of the Center for Advanced Biotechnology & Medicine, Piscataway, N.J.; and their coworkers, including Kalyan Das and Joseph D. Bauman. The researchers note that even as the enzyme’s binding pocket adjusts its shape through mutation, it remains tightly wrapped around TMC278, which is flexible enough to make complementary conformational changes. Arnold, Shatkin, and coworkers note that such mutual adaptability suggests the desirability of a more dynamic approach to drug design than is used conventionally. Shape modifications in protein targets and possible corresponding conformational adjustments in drugs should both be considered in the rational design of agents “intended to be broadly effective against targets that readily mutate and develop drug resistance,” the researchers write.—STU BORMAN
Among the new features being introduced is “In This Issue,” a collection of brief descriptions of selected articles from each month’s issue. The new “Spotlight” section showcases the latest toxicology news drawn from other journals. The January issue also features the first in a series of invited guest editorials. These articles will offer prominent scientists from around the world an opportunity to air their views on toxicology in their own countries. Hiroshi Yamazaki of the drug metabolism and pharmacokinetics laboratory at Showa Pharmaceutical University, in Tokyo, wrote the first editorial, on the topic of toxicological issues of importance in Japan. “Like everything else in our fast-moving world, toxicology is international in scope,” Marnett notes in an editorial in the issue. “However, the problems, opportunities, and challenges differ from continent to continent and, in some cases, from country to country.” The international guest editorials are “intended to illuminate these issues and to create an international community of educated readers with appreciation for their colleagues around the world,” he adds. In February, the journal will begin publishing additional perspectives written by members of the editorial advisory board about their latest research. The journal’s website has also been redesigned to enhance functionality and display capabilities.— SOPHIE ROVNER
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