Peptide-Based Drug Design

NMR of Peptides 105
Fig. 13. Proposed distribution of furylacryloyl phenylalanine (left) and captopril
(right) between the binding sites of ACE, as determined by trNOESY experiments.
(Adapted from ref. 76).
at cis proline at position 13. The turn is oriented at ∼90 ◦ in respect to the plane
of the �-strands.
The use of trNOESY experiments for screening purposes was first demonstrated
on carbohydrates binding to a lectin, an interaction that usually
is of medium to low affinity (75). Meyer et al. were able to identify a
binding carbohydrate from two carbohydrate libraries. In another experiment
Mayer et al. employed trNOESY experiments to determine the affinity and
subsite selectivity of derivatives of dipeptides and amino acids binding to the
angiotensin-converting enzyme (ACE). In their study they identified the highestaffinity
ligand from a small library of compounds. Using mixtures of amino acid
derivatives with and without additional dipeptides or one derivatized amino acid
and captopril, they were also able to determine the distribution of the peptides
between the different binding sites in the active site of ACE (76). Their proposal
for the distribution of furylacryloyl-phenylalanine and captopril between the
binding sites of ACE is shown in Fig. 13.
5.2. Cyclic RGD Peptides Binding to Integrin Studied by STD NMR
The RGD motif has long been known to be the principal binding motif of
several integrins (77). Aumailly et al. showed that the cyclic peptide c(RGDfV),
where f denotes d-phenylalanine (D-Phe), is a potent inhibitor of the integrin
�IIb�3 and determined the three-dimensional structure of the cyclic peptide from