Hairpin-shaped mimetics imitate the helical protein
that plays a role in the spread of HIV.
When a host cell is infected with HIV, the virus brings its own genetic
material into the host cell. This cell then replicates, reads the viral
RNA, and uses it as a blueprint to produce more viral proteins. Complete
viruses are then released to attack the next cells. A team of
researchers from the University of Zurich (Switzerland) and the
University of Washington (USA) has now developed a new potential
starting point for a drug that could intervene in this deadly cycle. As
reported in the journal Angewandte Chemie, it involves a hairpin-shaped
molecule that imitates the spatial structure of an important viral
protein and should thus stop the discharge of viral RNA from the cell
nucleus.
An important step in the lifecycle of HIV - and
a potential point of attack for treatment - is
as follows: The viral RNA produced in the nucleus of the host cell is
transported as a long strand out through pores in the cell membrane
into the cell�s cytoplasm, where it is translated into proteins or
packed into a viral shell. This discharge is an active process carried
out by a viral protein called Rev. For this process, many Rev units
have to attach to a binding site on the viral RNA, called the
Rev-responsive element (RRE). The search for an effective RRE-binding
inhibitor has thus far remained unsuccessful.
A small arginine-rich domain consisting of 17 amino acids allows the
Rev protein to recognize its binding site, a furrow on the RNA. Once
bound to the RNA, this domain adopts a helical form. It is this
protein structure that the team led by John A. Robinson and Gabriele
Varani wished to reverse engineer in order to disrupt the binding of
Rev to RRE.
The researchers produced a peptide mimetic, a molecule that imitates
the structure of the desired peptide. The group has previously shown
that α-helical peptides can be imitated by something called a
β-hairpin turn. The researchers attached side chains to the robust
scaffold formed by the �hairpin� so that the groups of atoms required
for molecular recognition are presented just as they are in the
original helical peptide.
A series of screening steps, starting from a small family of cyclic
hairpin peptide mimetics, led to the development of a structure that
firmly and correctly binds RRE. This compound also has the ability to
displace the Rev protein from Rev-RRE complexes.
�Hairpin peptide mimetics are a highly promising new class of drugs,�
says Robinson. �We hope that it will be possible to develop a drug
suitable for HIV treatment based on this foundation.�
Further Information and Source:
-
Kerstin Moehle, Dr., Zafiria Athanassiou, Dr., Krystyna Patora, Amy
Davidson, Gabriele Varani, Prof., John
A. Robinson, Prof.: Design of β-Hairpin
Peptidomimetics That Inhibit Binding of
α-Helical HIV-1 Rev Protein to
the Rev Response Element RNA.
In: Angewandte Chemie International Edition;
published Online: 24 Sep 2007; doi
10.1002/anie.200702801
