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non-natural, synthetic polymers
that can better withstand extreme
conditions in the field. The Agency
will hold a workshop next week to
describe recent successes and
discuss applications with potential
collaborators.
Biopolymers are large molecules
created by stringing together smaller
biochemical units, calledmonomers.
Proteins are biopolymers made
of hundreds or thousands of
monomers called amino acids. The
specific amino acids that are strung
together to make a protein, and their
linear order or “sequence,” define
the protein’s final three-dimensional
shape and, by virtue of that
shape, its function. For example,
insulin binds to specific molecular
structures on the surface of cells
precisely because of its specific 3D
(folded) shape, which is determined
by the sequence of its amino acid
building blocks. Performers in the
Fold F(x) program are leveraging
this concept of “sequence defines
shape defines function” to mimic
the activity of naturally occurring
biopolymers using completely new,
laboratory-produced
monomers.
Because these monomers are
synthetic, they can be designed to
be more robust than their natural
amino acid counterparts, opening
the door to making proteins with
new functional properties.
Since the late 1960s, researchers
worldwide have attempted to
design specific non-natural polymer
sequences that would fold into
specific three-dimensional shapes
and perform a desired medicinal
function. These one-off, targeted
attempts at “rational drug design”
have not yielded much success, in
large part because scientists still
have only a rudimentary means
of predicting how the multitude
of monomers in a biopolymer will
interact and fold on one another.
Performers in the Fold F(x) program
are taking a completely different
approach. Instead of trying to create
the one perfectly folded polymer that
will accomplish a desired biomedical
function, they are creating massive
suites of non-natural polymers with
at least a billion distinct sequences
that are hypothesized to fold into
some generally desirable class of
3D shapes. They are then screening
these polymer libraries with cutting-
edge sorting technologies to
identify which sequences in each
library bind to a particular target
of interest. The approach mimics
that of the human immune system,
which does not instantly produce
antibodies that bind specifically to
a newly encountered pathogen but
rather produces a shotgun blast of
varied antibodies, then amplifies
production of the antibody that
proves most effective at binding to
and disabling the attacking microbe.
There are significant challenges
to producing large libraries of
biopolymers and to screening for
those best suited to a desired task,
but the Fold F(x) program has been
enjoying a string of successes.
To date, six performer groups
have built billion-plus non-natural
polymer libraries and identified
members that bind to known targets
in application areas ranging from
biopharmaceutical
production
to biowarfare agent detection.
One group at the Massachusetts
Institute of Technology (MIT), for
example, created a non-natural
polymer with demonstrated thermal
and environmental stability that
can recognize the well-known
biowarfare agent anthrax. That
specific recognition may be
exploited to develop a rapid, field-
stable diagnostic test for anthrax.
MIT is now also screening its
non-natural polymer library in
collaboration with the U.S. Army
Medical Research Institute of
Infectious Diseases to create
synthetic biopolymers that bind
to Ebola, in the hope of creating
a totally new and robust Ebola
treatment. A separate effort at
Stanford University will use a newly
developed screening capability
based on high-throughput imaging
technology to identify non-natural
polymers that bind to inactivated
Burkholderia pseudomallei and
Burkholderia mallei, two bacterial
pathogens of significant interest to
the DoD.
Other teams have used the billion-
member library strategy of the
Fold F(x) program to generate
and rapidly identify synthetic
biopolymers that interact in very
specific ways with a number of
other targets. Some biopolymers
are predicted to be resistant to
digestion, for example, opening the
door to oral versions of medicines
that today must be injected because
they would otherwise break down
in the stomach. Others show
promise as temperature-resilient
compounds that could remain
potent for decades instead of
years, or shelf-stable diagnostics
that could someday replace
current counterparts that need to
be kept refrigerated. Collaborators
in DARPA’s Fold F(x) program
include University of California at
Irvine, Harvard University, Scripps
Research
Institute,
Lawrence
Berkeley National Laboratory, and
SRI International.