Download Fluorine-Adding Bacteria May Transform Natural Product Medicines

Fluorine-Adding Bacteria May
Transform Natural Product Medicines
The element fluorine is highly reactive,
toxic in many compounds, and almost
entirely irrelevant in biology. But chemists
who make medicines adore it. In 2012, three
of the top 10 best-selling drugs, with sales
of more than $20 billion, contained the element. By adding a touch of fluorine, chemists can fine-tune the properties of would-be
drugs, helping them selectively latch on to
their targets, avoid destruction by enzymes,
and wade through the fatty membranes surrounding cells. The trick works best with
small molecules; when chemists add fluorine to very large ones, such as the antibiotic
erythromycin and other large compounds
made by living things, it usually destroys
the function of the molecule.
Natural products chemists may soon
gain a new level of control—by enlisting
biology itself to add the fluorine. On page
1089, researchers at the University of California, Berkeley, and Stanford University
in Palo Alto, California, report that they’ve
engineered bacteria to make key fluorinecontaining starting materials and then
incorporate them into compounds called
polyketides, a diverse class of some 20,000
known molecules that contains some of
medicine’s most powerful antibiotics, antifungals, and insecticides.
“It’s exciting,” says Wilfred van der
Donk, a chemist at the University of Illinois, Urbana-Champaign. “Fluorine plays
a really important role in medicinal chemistry.” Many complex natural products are
Key atom. Drugs, such as the antichloresterol medication atorvastatin (left), use fluorine (green) to improve
their properties. Chemists can now do the same for large molecules, such as erythromycin (right).
Protein Designers Go Small
For living things, the task is a cinch: Make proteins that can bind tightly
and specifically to small molecules, such as the neurotransmitter nitric
oxide. Protein engineers would love to mimic the feat to create new
drugs and diagnostics. In the past, their best efforts at computer-aided
protein design fell short, because small molecules have few chemical
handles for proteins to latch onto.
No longer. This week in Nature, researchers led by computational
Tight fit. An atomic scale x-ray structure (magenta) of a protein bound to
a small molecule reveals a close match to the computer prediction (gray).
1052
potential drugs but have problems with toxicity, being cleared by the body too quickly,
and other concerns, van der Donk notes.
Chemists would love to have the power of
natural products yet be able to tailor them
like small molecules. “Now you have the
best of both worlds if you can do this efficiently,” van der Donk says.
Fluorine’s medicinal prowess stems
from its eagerness to snag an electron from
another atom, forming a very tight bond.
Because bonds between fluorine and carbon
are so hard to disrupt, they make organic
compounds less susceptible to degradation by enzymes called P450s that normally
break down small drug molecules quickly.
6 SEPTEMBER 2013
VOL 341
protein designer David Baker at the University of Washington, Seattle,
and structural biologist Barry Stoddard of the Fred Hutchinson Cancer
Research Center in Seattle report that they’ve designed a protein to
tightly grab a heart drug steroid called digoxigenin, while excluding
similar steroids such as digitoxigenin (even the name is almost indistinguishable) and progesterone.
“It’s a very impressive result,” says Brian Kuhlman, a biochemist at
the University of North Carolina, Chapel Hill. And it is long-awaited.
Ten years ago, for example, Duke University researchers published two
papers claiming that they had created a protein tailored to a specific
small molecule, only to have a former postdoctoral assistant from the
same lab challenge the results in 2009.
Baker and his group succeeded using a multipronged approach.
Among the most important considerations, Baker says, they designed
their algorithm to pay special attention to weak hydrogen bonds and
van der Waals interactions between particular amino acids in the protein and water-loving “polar” portions of the molecule. They also
designed the binding pocket that grabs digoxigenin to be fairly rigid,
which makes the protein more selective for the compound.
The new work holds out hope that protein designers will be able
to use similar techniques to design novel therapeutics that sop up
unwanted small molecules in the body, as well as diagnostics that can
find similarly small targets. But more than that, Kuhlman says, the work
restores protein engineers’ confidence that they can solve one of their
greatest challenges. “It’s a very powerful example that in some cases
we can do this.”
–ROBERT F. SERVICE
SCIENCE
Published by AAAS
www.sciencemag.org
CREDITS: QUTEMOL/WIKIMEDIA COMMONS; GIORGIOGP2/WIKIMEDIA COMMONS; C.E. TINBERG ET AL., NATURE 501 (5 SEPTEMBER 2013) © NATURE PUBLISHING GROUP
S Y N T H E T I C B I O LO G Y
Downloaded from www.sciencemag.org on September 24, 2013
NEWS&ANALYSIS