OncoLog, Volume 46, Number 11/12, November/December 2001 Page: 4
12 p. : ill.View a full description of this periodical.
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Highly Selective Synthetic Binding Agei
Tools Are Now Available to Determine the Relaby Kerry L. Wright
D NA in its most
traditional form is
called B-DNA,
otherwise known
as right-handed DNA, the kind
of DNA that appears in text-
books and is by far the most
prevalent in the body. On many
occasions, books, newspapers,
and even prominent scientific
journals have mistakenly in-
verted images of B-DNA and
reversed its twists, publishing
illustrations of left-handed
helices instead of the typical
right-handed ones. While those
images do not represent any
actual DNA configuration, the
image of left-handed DNA in
this article (page 5) is not a
mistake.
Collaboration among researchers at
the University of Mississippi Medical
Center, the James Graham Brown
Cancer Center at the University of
Louisville, and The University of Texas
M. D. Anderson Cancer Center has led
to the creation of the first compound
that binds Z-DNA, a left-handed form
of DNA, with selective affinity. The
compound, called WP900, could lead
to the development of a new class of
anticancer agents that target Z-DNA.
In turn, this effort is part of a broader
program aimed at using small molecules
to target and control expression, at the
transcriptional level, of genes important
to the development and progression
of cancer.
For years, Z-DNA was an enigma.
First visualized by researchers at the
Massachusetts Institute of Technology
in the 1970s, Z-DNA was thought by
4 / OncoLogmany at the time to be a fluke, an
artifact of B-DNA rather than a
biologically significant form of
genetic material. Then, in 1999,
the same persistent scientists
showed that left-handed DNA was
found inside living cells: It turned
out that B-DNA could actually
transform into Z-DNA, specifically
during the transcription of genes.
Though only present for a short
time before it coils back into the
right-handed form, Z-DNA is the
target of an RNA-editing enzyme
called adenosine deaminase that
uses the left-handed genetic
material as an anchor while it slides
along newly transcribed RNA,
making small changes that eventu-
ally create modified proteins. This
activity provided the first inkling
that although Z-DNA most likely
makes up only a tiny percentage of
the DNA in cells, it might have a
very important biological function.
But how could scientists
selectively study Z-DNA?
Waldemar Priebe, Ph.D., a
professor in the Department of
Bioimmunotherapy at M. D.
Anderson, was asking the same
question. Although compounds
were available that could bind B-
DNA alone or both B-DNA and
Z-DNA, there weren't any that
selectively bound Z-DNA-
until WP900.
After several years of collabora-
tion between Dr. Priebe,
Jonathan B. Chaires, Ph.D.
(University of Mississippi Medical
Center), and, more recently,
John 0. Trent, Ph.D. (University of
Louisville), WP900 was synthesized
through an arduous 32-step process an
then molecularly modeled. The ration
WP900 was designed as a mirror imag
(or an enantiomer, in chemical terms)
of naturally occurring daunorubicin, a
common anticancer drug that selective
binds right-handed DNA. Although I
DNA and Z-DNA are not exact mirrc'<iiiI
Left) Dr. Waldemar Priebe, a professor in the Deg
separate a compound from the reaction mixture-a s
rent such as WP900.
Top right) Shown with Dr. Priebe (third from the left
f DNA-binding agents. Pictured in the M. D. Anders
om the right), a research associate in the Department
ght) Joanna Dziewiszek, Sangkyou Lee, Sla
Bottom right) WP900 is a synthetic enantiomer of dao
left-handed form of DNA that may one day be a targ(
-DNA is shown at left.
images of each other, WP900 still bound,
with great selectivity, to Z-DNA but not
to B-DNA in vitro, and it even caused
the allosteric conversion of B-DNA
oligomers into the left-handed form.
"For a long time, it was speculated
that Z-DNA was important, but there
were no good tools to investigate its
biological role. WP900 provided the
initial opening into this area," said
Dr. Priebe.
Now that compounds (and, evenk
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 46, Number 11/12, November/December 2001, periodical, November 2001; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth903627/m1/8/: accessed July 18, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu.; crediting UNT Libraries Government Documents Department.