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NEWS OF THE WEEKChung’s team useda computer todock two differentconformations ofresveratrol (pinkand turquoise)into the metalcontainingcatalytic pocket of aphosphodiesterase.COURTESY OF JAY CHUNGHOW RESVERATROLWORKSBIOCHEMISTRY: Molecule’s metaboliceffects result from acting directly onphosphodiesterases, not sirtuinsHOCHALK UP the red wine compoundresveratrol’s presumedhealth benefits to a direct blockadeof phosphodiesterase enzymes, reports a OHmulti-institution team ( Cell, DOI: 10.1016/j.cell.2012.01.017). The researchers, led by NIHbiologist Jay H. Chung , say their study clarifies confusingevidence about the biochemistry of resveratrol.The study’s results point to new avenues of preventingage-associated metabolic diseases in people, saysUniversity of Wisconsin, Madison, calorie restrictionresearcher Richard Weindruch , who was not involved inthe NIH research. In principle, preventing such diseasescould extend human life spans.Resveratrol is known to mimic the antidiabetic effectsof calorie restriction in rodents, and it boosts lifespan in flies and worms. Whether resveratrol is beneficialto humans is not clear, but a recent study suggestsit also mimics the effects of calorie restriction in obeseResveratrolpeople ( Cell Metab., DOI: 10.1016/j.cmet.2011.10.002 ).Resveratrol was thought to work in animals by directlyactivating sirtuin enzymes, which clip acetyl groupsfrom proteins, researchers say. From that idea grew Sirtris,a biotech company that GlaxoSmithKline acquiredfor more than $700 million in 2008. Since then the sirtuinclaim has come under heavy scrutiny as scientistsOHhave found that they can’t reproduce theearlier pro-sirtuin evidence.Chung and coworkers used cellular assaysand animal tests to show that resveratrolincreases levels of cyclic AMP. The cyclic AMPboost happens, they conclude, because resveratrolblocks phosphodiesterase enzymes that break downcyclic AMP. Resveratrol does indeed activatesirtuin enzymes, Chung says, but indirectly, furtherdownstream in the phosphodiesterase-mediatedpathway.This work points to one pathway resveratrol mayuse to activate sirtuins but doesn’t prove it’s the onlypathway, adds sirtuin expert, and Sirtris scientific advisoryboard cochair, Leonard P. Guarente at MIT.Chung notes that it is impossible to prove thatno other mechanism exists but says when his teamblocked the key phosphodiesterase enzyme in muscle,it completely reproduced resveratrol’s effects. Thisstrongly suggests that when it comes to metabolic effects,“the phosphodiesterase pathway is the majorpathway,” he says. — CARMEN DRAHLA computermodel depictsnanoclusters ofantibodies againstpertussis toxin;each disk in theclusters representsa single antibody.EASY-TO-USEPROTEIN DRUGSDRUG DELIVERY: Nanoclusters enableinjectable suspensions of proteinsTO IMPROVE DELIVERY of protein drugs, researchershave developed a way to make highlyconcentrated, injectable suspensions of proteins( ACS Nano , DOI: 10.1021/nn204166z .When patients need a high dose of a protein drug,they usually receive an intravenous drip.Some rheumatoid arthritis patients, for example,must go to a clinic for regular intravenoustreatment, which is expensive, stressful,and time-consuming. Simple, quick injectionsunder the skin often aren’t feasible, becausehighly concentrated protein solutions becometoo viscous.In solution, proteins start to unfold andclump at concentrations around 100 mg/mL.But inside cells, proteins abound at concentrationsfour times as high and don’t normallyform clumps. By mimicking the crowdedenvironment inside cells, Keith P. JohnstonACS NANOof the University of Texas, Austin , and colleagues canpack a high dose of protein drugs in a syringe.To re-create the crowding in a cell, the researchersencouraged the proteins to assemble into nanosizedclusters. First they adjusted the pH of the proteins’ solutionso that the molecules had almost no net surfacecharge. Then they added trehalose, a nontoxic sugar,in sufficient quantities to push the proteins together.With no surface charge, the proteins don’t repel oneanother, and they form nanoclusters measuring a fewhundred nanometers across.The scientists characterized nanocluster suspensionsof three different proteins, including an antibodythat binds the pertussis toxin, at concentrations as highas 700 mg/mL. When they injected the antibody nanoclustersunder the skin of mice, the nanoclusters tooklonger to diffuse into the bloodstream than did conventionalprotein solutions, but once in the bloodstream,both protein formulations had similar activities andlifetimes.Theodore W. Randolph of the University of Colorado,Boulder , says that to demonstrate that the nanoclustermethod is practical, the researchers will have to showthat the nanoclusters have at least a two-year shelflife and that the method works for other proteins aswell. The Texas group is working on further tests. —KATHERINE BOURZAC , Special to C&ENReprinted from C&EN, Feb. 6, 2012 (both)WWW.CEN-ONLINE.ORG 6 MARCH 2012