Reading C&EN

1. From February 20, 2012 Reading C&EN By zhangmin 2012-02-26

2. DRUGS TARGET EPILEPTIC ABSENCE SEIZURES Two rationally designed drugs effectively treat a form of epilepsy癫痫症known as absence seizures意识丧失型癫痫 in rats with a genetic predisposition to the disorder. During absence seizures, which are most common in children and adolescents, a person momentarily loses awareness and is unresponsive. Current absence seizure drugs act on broad ranges of targets, and they cause a host of side effects . —Sic. Transl. Med.,DOI: 10.1126/scitranslmed.3003120

3. Absence seizures stem from the concerted over-firing of neurons in the thalamus丘脑. Recent evidence suggests that a subset of Ca2+ channels, known as T-type, in the neurons act as conduits管道to propagate传播this hyperactive 极度活跃firing. Terrance P. Snutch of the University of British Columbia, Elizabeth Tringham of pharmaceutical 制药公司firm Zalicus , and colleagues started their design with an N-type Ca2+ channel-blocking pharmacophore药效团.

4. They assembled compound libraries, finding two molecules designated Z941 and Z944 that block T-type Ca2+ channels in thalamus neurons. They tested the compounds on epileptic rats, showing that the drugs suppressed absence seizures by 85 to 90%. The researchers say the drugs’ action appears to be different from that of current absence seizure drugs. — EKW

5. DELIVERY VIA DNA NANOBOTS Just as a postal worker knows to deliver a package to a specified address, a new type of nanoscale robot can deliver therapeutic cargo治疗药物specifically to cancer cells. The nanobot, made from DNA, could be used for targeted drug delivery, taking molecules to the surface of specific cells. —Science, DOI: 10.1126/science.1214081

6. A robot is something that senses and reacts to its environment, explains George M. Church, the Harvard Medical School professor who devised设计 the DNA nanobot along with colleagues Shawn M. Douglas. The Harvard team’s robot is a hexagonal barrelthat can carry a variety of payloads有效载荷 and is held together by two “locks” made from DNA aptamers核酸适配体, which are short oligonucleotide strands低聚核苷酸链 that can bind捆绑 antigen抗原 targets.

7. When these locks encounter antigens on the surface of certain cells, the antigens bind each DNA aptamer, springing弹起 the locks. The robot opens and delivers its cargo. Because of their targeting ability, these nanobots are “considerably smarter than your average therapeutic治疗的 drug,” Church says. The researchers built the robot using DNA origami DNA结构微型芯片, a technique in which short strands of DNA “staple” one long strand into a predetermined shape.It’s been used previously to make novelty structures, such as boxes and smiley faces. The nanobot is one of the first examples of the technique’s use to build a practical device.

8. “The report convincingly provides a proof of principle that DNA origami has the capacity to create highly intelligent drugs that only become activated when encountering diseased cells,” comments Jorgen Kjems, a DNA origami expert at the University of Aarhus, in Denmark. “This will inevitably lower the toxicity and thereby the side effects of therapeutic drugs carried by the device. The next step will be to harness DNA nanorobots to withstand the harsh environmentof living organisms and prove that they can go all theway to create new and more effective nanomedicines for animals and humans.” — BETHANY HALFORD

9. MEMORIES’ SWEET ORIGINS Researchers have found that O- linked β- N –acetyl-D-glucosamine ( O-GlcNAc) discourages memory formation when it’s attached to the transcription factor CREB and that memory improves when the sugar is removed or absent. The finding reveals a previously unknown sugar-based mechanism for regulating控制 gene expression, neural development神经发育, and memory. It could lead to new ways to enhance memory or to reduce memory loss among patients with diseases such as Alzheimer’s老年痴呆症. —Nat. Chem. Biol., DOI: 10.1038/nchembio.770

10. O- GlcNAc modification of proteins was known to influence brain development, neuronal signaling神经元传递, and neurodegeneration神经退化. But how it affects such processes on a molecular level had been uncertain. Using a sugar-tagging糖标记 technique they developed, carbohydrate chemist Linda C. Hsieh-Wilson of California Institute of Technology and coworkers have shown for the first time the profound effects of O- GlcNAc on the transcription factor CREB. Working with mice, they found that gene expression, neuronal axonand dendrite growth, and memory formation are reduced by CREB glycosylation 糖基化 with O-GlcNAc and promoted by blocking that glycosylation.

11. The same three processes are enhanced by CREBphosphorylation磷酸化作用and reduced by CREBdephosphorylation脱磷酸作用. Phosphate磷酸盐and O- GlcNAc appear to work together, albeit in an opposite way. Together with many prior studies, the work shows “how the fields of neurobiology神经生物学, transcription, and signaling need to pay attention to this ubiquitous sugar modification of proteins to understand biology at the molecular level,” says O- GlcNAc expert Gerald W. Hart of Johns Hopkins University. “Focusing only on phosphorylation will reveal only part of the story.”

12. How memories are made “is one of the great biological mysteries,” says another O- GlcNAc specialist, John A. Hanover of NIH. The new findings “provide an importantclue” to better understand that process. — STU BORMAN

13. Thank you !