Transcript made from DNA aptamers核酸适配体, which are short

Reading C&EN
From February 20, 2012
By zhangmin
2012-02-26
DRUGS TARGET EPILEPTIC
ABSENCE SEIZURES
—Sic. Transl. Med.,DOI: 10.1126/scitranslmed.3003120
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 .
Absence seizures stem from the concerted overfiring 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.
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
DELIVERY VIA DNA NANOBOTS
—Science, DOI: 10.1126/science.1214081
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.
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 barrel that 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.
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.
“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 environment of
living organisms and prove that they can go all the
way to create new and more effective
nanomedicines for animals and humans.” —
BETHANY HALFORD
MEMORIES’ SWEET ORIGINS
—Nat. Chem. Biol., DOI: 10.1038/nchembio.770
Researchers have found that O- linked β- N –acetyl-Dglucosamine ( 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.
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 axon and dendrite growth, and memory formation
are reduced by CREB glycosylation 糖基化 with O-GlcNAc
and promoted by blocking that glycosylation.
The same three processes are
enhanced by CREB phosphorylation磷
酸化作用and reduced by CREB
dephosphorylation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.”
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
Thank you !