T
hedistribution of medicines in developing coun-
tries is a logistical and economic challenge.Medi-
cinesmust be cheaply produced so that they are
affordable for people with little income, and
then they must be maintained in an active form
throughout transport and storage.
An enticing and economical alternative to lab-based phar-
maceuticals is to harness plants to produce orally active edible
meds.Takingyour meds could be as simple aseating your greens
or sprinkling some sunlower seeds on your breakfast cereal.
However, this dream can only become a reality if plants can be
engineered to consistently manufacture medicines in an orally
available form.
Proteins and peptides meet the irst of these criteria: they can
be readily engineered in plants because their genetic code can
be manipulated to produce a given amino acid sequence. Protein-
based medicines also offer a larger surface area to interact with
their targets, leading to greater speciicity and fewer off-target
effects. Protein-based pharmaceuticals currently on the market
include synthetic insulin to treat diabetes and the anti-HIV
medication enfuvirtide.
However, proteins generally don’t meet the second criteria.
They are often ineffective when administered orally because
they aren’t stable in biological luids and are rapidly broken
down into inactive fragments before they reach their target.
Tantalising early evidence that orally available peptides could
be delivered in plant material comes from traditional medi-
cines. In the 1960s, Norwegian doctor Lorents Gran observed
that women in the Democratic Republic of the Congo used
the leaves of a native plant, kalata-kalata (Oldenlandia ainis),
to produce a medicinal tea that was given to women in child-
birth to accelerate labour. The active ingredient was incred-
ibly stable and remained orally available even after boiling. This
was soon identiied as a 29 amino acid peptide, but it was some
years before the structure of this peptide was solved, revealing
a rigid set of cross-links as well as a circular backbone that
provided a molecular basis for its incredible stability.The circular nature of this peptide was particularly unusual
since peptides are more typically linear, with distinct termini.
The circular peptide backbone contributes to its stability by
introducing structural constraints while making the ends of
the peptide inaccessible to proteases that degrade peptides into
smaller parts. Circular peptides of this family, named cyclotides,
have subsequently been isolated from numerous plants and
ascribed a range of bioactivities against insects, molluscs, nema-
todes and HIV. Cyclotides can also be engineered to exhibit
other functions.
The rigid core of cyclotides is surrounded by loops that can
be modiied. Grafting of new bioactive peptides within this
scaffold can improve the oral availability of otherwise unstable
peptides. The most recent example of this was the engineering
of a cyclotide scaffold to impart speciic activity against recep-
tors involved in inlammatory pain. This new peptide was orally
available in mouse models.
Circularisation can also been applied to peptides that are
naturally linear. This has successfully increased the potency,
oral availability and selectivity of a linear peptide derived from
the venom of cone snails. The circularised peptide was 120
times more potent than gabapentin, a drug in clinical use for
the treatment of neuropathic pain.
These examples highlight the excellent potential of both
cyclotide scaffolds and the more generally applicable circular-
isation of peptides to produce potent, stable drugs.
Cyclic peptides are eiciently produced in high amounts in24 | JUNE 2016
Phar ed Meds
KAREN HARRIS & MARILYN ANDERSONSome clever chemistry is turning plants into
pharmaceutical factories that could enable remote
communities in developing countries to grow and
store stable medicines cheaply.MaksymYe