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RESEARCH BRIEFS
Small Molecule Blocks Herpes ReplicationLife at the molecular level is a social whirl, with proteins constantly touching, embracing, and otherwise relating to one another. Protein-protein interactions keep organisms alive, and this is as true of disease-causing organisms as it is of their hosts. For years, researchers held out hope that by selectively disrupting these interactions with small molecules, they might kill pathogens such as bacteria and viruses. But few such molecules have been found. And many researchers, daunted by the sheer size of the interacting protein surfaces, have assumed that their molecules may be too small to stop the proteins from coming together.Their doubts may be unfounded, at least in some cases. Beatrice Pilger, Can Cui, and Donald Coen have identified a small molecule that successfully interrupts a key protein-protein interaction in one of the peskiest microbes of all, herpes simplex virus (HSV). What is more, the researchers report in the May Chemistry & Biology that the molecule prevents the virus from replicating.
The researchers had reason to believe the small-molecule approach might work. In earlier research, Coen, HMS professor of biological chemistry and molecular pharmacology, and colleagues had found that the interaction between two critical HSV proteins, Pol and UL42, was blocked in mutants carrying a single amino acid change. Thinking that a small molecule could do the work of a point mutation, Pilger, then a research fellow in biological chemistry and molecular pharmacology at HMS, screened 16,000 compounds to see if any would cause the two proteins to come apart. Using a fluorescent polarization assay, she netted several candidates. One, BP5, was found to be a viable blocking and antiviral agent. Though BP5 is too toxic to be used in people, it could serve as a prototype for safer drugs, a possibility Coen, Cui, a graduate student in the Biological and Biomedical Sciences program, and colleagues are currently exploring. In fact, the approach might be effective against other microbes and even against cancer cells. "There the medical need is greater," said Coen. --Misia Landau
Test Ratio Predicts Breast Cancer Patients Who Respond to TamoxifenThe estrogen receptor modulator tamoxifen has been used successfully to treat human breast cancer for more than two decades. Many women who receive the medication will remain cancer free for years, but a considerable proportion, about 40 percent, will fail to respond altogether or will develop drug resistance and relapse. If only doctors could tell in advance who the nonresponders might be, they could justifiably offer more aggressive therapy at the outset.In June's Cancer Cell, Dennis Sgroi, HMS associate professor of pathology at Massachusetts General Hospital, and colleagues report that the relative expression of just two genes, the homeobox gene HOXB13 and the gene for the interleukin 17B receptor (IL17BR), can almost always distinguish responder tumors from those of nonresponders. Sgroi, with researchers from California's Arcturus Bioscience, including first author Xiao-Jun Ma, used DNA microarrays to measure gene expression profiles of breast cancer cell biopsies from 60 patients who had been treated with tamoxifen. Of more than 20,000 genes analyzed, Ma found that HOXB13 was more robustly expressed in cells isolated from patients who experienced a recurrence of cancer, while for IL17BR, the opposite was true, it was overexpressed in nonrecurrent cases. Putting the data together, Ma found that the HOXB13:IL17BR ratio was a powerful predictor of tamoxifen response. The expression ratio of these two genes offers the basis for a simple clinical test. As proof of principle, the authors used quantitative polymerase chain reaction experiments to determine HOXB13:IL17BR in samples from an additional 20 breast cancer cases. The ratio correctly predicted the outcome in 80 percent, or 16 cases. Those with a low ratio had a greater than 80 percent chance of surviving to six and a half years post-treatment, while for those with a high ratio, the chances of survival were less than 20 percent. "We believe that this work is important because the assay may prove helpful in identifying at-risk patients who might benefit from alternative hormonal or chemotherapeutic interventions," said Sgroi. "We also believe that this may represent a form of 'personalized' molecular medicine, the goal of which is to increase the overall absolute benefit, while minimizing side effects," he added. The work may also lead to new treatment targets. In collaboration with Steve Isakoff, a clinical fellow at the Dana-Farber Cancer Institute, and Joan Brugge, HMS professor and acting chair of the Department of Cell Biology, Sgroi is currently pursuing the potential role of HOXB13 in breast cancer progression and tamoxifen resistance. --Tom Fagan |
