New technique for more efficient drug development
19 Jan 2011
A tiny polypeptide that can bind to virtually any
target-seeking organic molecule used for drug development could
considerably shorten the time taken to determine the suitability of a
target molecule as a useful drug.
Developing new drugs is a highly costly and time-consuming process.
Of 20 candidates, 19 are normally rejected because they don’t work
or have unwanted side effects. Now a research team led by Professor
Lars Baltzer at Uppsala University has produced a tiny molecular
“binder” that has the potential to change this landscape radically.
The study, published in the journal Angewandte Chemie,
presents the concept of a tiny polypeptide consisting of 42 amino
acids to which virtually any target-seeking organic molecule can be
bound. In the body it then seeks out the designated sites to be
What’s unique about the polypeptide is that it dramatically enhances
the properties of the little molecule in a simple and very general
way. It produces superbinders. They bind more strongly and more
specifically than other alternatives, says Lars Baltzer, professor
of organic chemistry, who believes it will be possible to rapidly
develop new drugs much more readily with this new concept.
The whole concept goes against the grain of what is usually done in
drug development. Traditionally, it’s usually a matter of
synthesizing drugs from A to Z, with certain requirements needing to
be met in order to succeed. Drugs should be low molecular weight
(500 Daltons), be highly fat soluble, and have no more than ten
binding sites in order to pass through the cell membrane. But the
majority are ineffective or toxic, and nowadays there are also ways
to get larger molecules through cell membranes.
Recently, therapeutic antibodies have emerged as an alternative.
They’re large (150,000 Da) and bind to the outside of cells, which
they then "block".
The new peptide is 5,000 Da or only 1/30
as large as a typical antibody, which is smaller than was thought
possible. But according to Lars Baltzer nature has always signalled
that this should work. The human growth factor hGH uses 35 amino
acids to bind to its receptor, but it turns out that only six of
them are critical. The rest can be replaced without significantly
changing the function. There’s really nothing very special about
placing a general peptide on a small molecule, but nobody has done
it before, he says.
In this study the peptide was
successfully bound to the inflammation marker CRP, which is an
indicator of a risk of premature death in heart patients, among
other things. Several other studies are underway and are proving to
be equally successful.
These findings are of great
importance to industry, and several large companies have shown their
interest. The spin-out company that was previously formed out of
Baltzer’s research team is now going to further develop the concept
to be able to help the drug industry determine at a considerably
earlier stage than today whether a drug candidate is worth pursuing