Abstract
In our initial studies we could show that two-armed receptors based on a
vinylogous sulfonyl tripeptide and the corresponding tripeptide interact
sequence-specifically with tripeptides. These results encouraged us to
reverse the approach and to screen a combinatorial library of molecules
with a similar design to find selective receptors for given ligands. We
synthesized an encoded combinatorial receptor library using
chenodeoxycholic acid as a scaffold that carries two combinatorial
tripeptide chains. To investigate the importance of the cholic acid
template for the binding properties of the molecular forceps, we replaced
the rigid cholic acid scaffold by a flexible polymethylene chain to obtain
a "flexible library". Although members of this library still show affinity
towards Leu-enkephalin, the specificity and the strength of the interaction
were distinctly lower, thus underlining the influence of structural
rigidity in the molecular forceps for the selective recognition of small
flexible peptides.
We are currently engaged in the evaluation of the possibilities of using
such molecules for the modulation of biological processes. We are studying
the capacity of these molecular forceps to bind selectively to epitopes of
physiologically important proteins, such as the carboxy-terminus of Ras,
and block the biological processes these epitopes are involved in, e.g.
farnesylation of the CaaX-box and localization of the RAS-protein.
