Bentuk - perubahan enzim
menunjukkan dosis seberapa kecil dari anti - HIV mungkin mengobati Alzheimer
roadmap molekul memberikan
bukti kunci yang mendukung usulan
untuk memulai uji klinis dari efavirenz
sebagai pengobatan Alzheimer
Date:
June 28, 2016
Source:
National Institute of Standards
and Technology (NIST)
Summary:
Obat anti-HIV disetujui terkait untuk enzim yang sudah bertanggung jawab untuk sekitar 80 persen dari eliminasi kolesterol dari otak manusia, laporan para ilmuwan . Diperoleh dengan cutting-edge teknologi atom-substitusi disebut pertukaran hidrogen-deuterium, peta jalan molekul menunjukkan bagaimana sejumlah kecil obat dapat menendang enzim, yang disebut CYP46A1, ke gear yang lebih tinggi.
.........................
Untuk jalur yang menjanjikan untuk mengobati pasien Alzheimer, "bertujuan sini."
Itulah yang Institut Nasional Standar Teknologi (NIST)
teliti yang menyarankan kolaborator berburu untuk
molekul yang, dengan menghubungkan ke enzim yang
biasanya terjadi, rev up kapasitas otak untuk
membersihkan kolesterol - dorongan yang terkait
dengan perbaikan dalam memori dan manfaat lainnya
pada hewan .
Target ditunjukkan oleh para ilmuwan NIST adalah dimana disetujui
obat nti-HIV - efavirenz - terkait untuk enzim yang sudah bertanggung jawab
untuk sekitar 80 persen dari eliminasi kolesterol dari otak manusia.
Diperoleh dengan cutting-edge teknologi atom-substitusi pertukaran
disebut hidrogen-deuterium (HDX), peta jalan molekul menunjukkan
bagaimana sejumlah kecil obat dapat menendang enzim,
yang disebut CYP46A1, ke gear yang lebih tinggi.
.........................
.......................................
Bentuk - perubahan enzim menunjukkan dosis seberapa kecil dari anti -
HIV mungkin mengobati Alzheimer,Shape-changing enzyme ,HIV drug , Alzheimer's,Molecular roadmap , clinical trials ,anti – HIV,efavirenz , cholesterol elimination,hydrogen-deuterium exchange, CYP46A1,
cutting-edge atom-substitution technology, called hydrogen-deuterium exchange
(HDX), NIST ,efavirenz ,cutting-edge atom-substitution
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Shape-changing enzyme suggests how
small doses of anti-HIV drug might treat Alzheimer's
Molecular roadmap provides key
evidence supporting proposal to launch clinical trials of efavirenz as an Alzheimer's
treatment
Date:
June 28, 2016
Source:
National Institute of Standards
and Technology (NIST)
Summary:
An approved anti-HIV drug latches to the enzyme already
responsible for about 80 percent of the cholesterol elimination from the human
brain, report scientists. Obtained with a cutting-edge atom-substitution
technology called hydrogen-deuterium exchange, the molecular roadmap shows how
small amounts of the drug can kick the enzyme, called CYP46A1, into higher
gear.
.........................
For a promising pathway to treating
Alzheimer's patients, "aim here." That's what National Institute of
Standards of Technology (NIST) researchers advised collaborators hunting for
molecules that, by linking to a normally occurring enzyme, rev up the brain's
capacity for clearing cholesterol--a boost associated with improvements in
memory and other benefits in animal studies.
The target pinpointed by the NIST scientists is where an approved anti-HIV
drug -- efavirenz -- latches to the enzyme already responsible for about 80
percent of the cholesterol elimination from the human brain. Obtained with a
cutting-edge atom-substitution technology called hydrogen-deuterium exchange
(HDX), the molecular roadmap shows how small amounts of the drug can kick the
enzyme, called CYP46A1, into higher gear.
With this information, a team led by Irina Pikuleva of Case Western Reserve
University now has the full story behind the drug's mechanism of action, key
evidence in their proposal to launch clinical trials of efavirenz as an Alzheimer's
treatment. The analytical sleuthing that exposed the dynamics of the
cholesterol-clearing connection was reported in a recent issue of the Journal
of Biological Chemistry.
Analyses of NIST's HDX data and follow-on experiments helped to explain
why, in studies of mice, tiny doses of efavirenz ramped up CYP46A1's
cholesterol-removal capability while larger doses had an inhibiting effect.
The explanation: At low doses, efavirenz binds to a site on the enzyme that
boosts cholesterol breakdown at another location on the enzyme, an increase
enabled by changes in shape initiated by the drug. At higher doses, however,
drug molecules begin to compete with cholesterol for the same site where
cholesterol normally binds.
The shape-changing effect of efavirenz "is a classic example of a
basic tenet of biology -- structure determines function," Pikuleva said.
And the effect can be dramatic.
In mouse studies, the enzyme-drug connection triggered a 40 percent
increase in cholesterol breakdown and removal from the brain. In people, the
boost is likely to be significantly higher, Pikuleva said, since the enzyme
plays a larger disposal role in the human brain than in the mouse's.
Studies of over the past 15 years persuaded Pikuleva's team to pursue an
Alzheimer's treatment strategy focused on ratcheting up the
cholesterol-clearing capabilities of CYP46A1, part of a large family of
iron-containing enzymes that strongly influence how the body processes drugs.
Studies by other scientists that used genetic manipulations in mouse models
of Alzheimer's disease showed that cranking up CYP46A1's activity reduced
development of plaque, or clumps of protein pieces called beta amyloids. These
studies also reported improvements in memory and learning. And, even in
plaque-free, normal mice, increased cholesterol removal resulted in memory
improvement.
Conversely, mouse studies also found that suppressing CYP46A1 led to
learning deficiencies.Focusing on efavirenz as part of its strategy to
"repurpose" already-approved drugs, the Case Western team set out to
uncover how the drug stimulates the enzyme's activity. Computational
simulations and modeling suggested more than 30 locations on the enzyme where
efavirenz molecule might bind.
Seeking to winnow down the options, Pikuleva turned to Kyle Anderson and
colleagues at the Institute for Bioscience and Biotechnology Research, a
partnership between NIST and the University of Maryland.
In HDX analyses, proteins are immersed in "heavy water," in which
normal hydrogen, containing a single proton in its nucleus, is replaced by
deuterium, a rarer type of hydrogen whose nucleus holds both a proton and
neutron. Protein and heavy water exchange hydrogen and deuterium. As the
protein swaps out hydrogen for heavier deuterium, its mass increases. The process
involves a series of steps that include quenching--or locking in the deuterium
in the protein--and then breaking the protein into electrically charged
fragments for analysis. With a device called a mass spectrometer, researchers
can measure the mass of these fragments to determine how quickly these protein
pieces exchange hydrogen for deuterium. A protein fragment that is largely
exposed to water will have a fast exchange rate, but a fragment that comes from
a site buried inside the protein or is covered up by a molecule binding to the
protein will have a slower exchange rate.
"HDX mass spectrometry opens a window that allows you to look in on
how proteins behave under physiologically relevant conditions," Anderson
explained. "It provides the pieces to a puzzle that you can assemble to
show how their three-dimensional shape changes over time."
The NIST team used HDX to compare and contrast CYP46A1 in four different
states: alone, with cholesterol only, with efavirenz only, and with cholesterol
and efavirenz. Subsequent analyses of the resulting torrents of experimental
data--a computationally intensive process that Anderson performed in triplicate
to ensure accuracy--revealed not only where the drug attached to the enzyme but
also how the cholesterol-binding site adjusted in response. The structural
changes enabled CYP46A1 to bind cholesterol molecules more tightly than in the
absence of the drug.
Following up with a study using a different method, Pikuleva's team further
confirmed the site of efavirenz binding as determined with HDX. The evidence
strongly suggests, she said, at doses a hundred times lower than prescribed for
treating HIV, efavirenz might be an effective therapy for stimulating
cholesterol turnover from the brain and slowing or preventing Alzheimer's
disease.
Pikuleva and colleagues now are seeking to obtain funding for a clinical
trial on humans to investigate the effects of small doses of efavirenz.
Story Source:
The above post is reprinted from materials provided
byNational Institute of Standards and
Technology (NIST).Note: Materials may be edited for
content and length.
Journal Reference:
1. Kyle W.
Anderson, Natalia Mast, Jeffrey W. Hudgens, Joseph B. Lin, Illarion V. Turko,
Irina A. Pikuleva. Mapping of the Allosteric Site in Cholesterol
Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. Journal
of Biological Chemistry, 2016; 291 (22): 11876 DOI: 10.1074/jbc.M116.723577