Abstract
The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide-protease interactions will aid future designs of bicyclic peptide protease inhibitors.
| Translated title of the contribution | Bicyklisk peptid-hæmmer af urokinase-type plasminogen-aktivator: xxx |
|---|---|
| Original language | English |
| Journal | ChemBioChem |
| Volume | 14 |
| Issue | 16 |
| Pages (from-to) | 2179–2188 |
| Number of pages | 10 |
| ISSN | 1439-4227 |
| DOIs | |
| Publication status | Published - 2 Oct 2013 |
Keywords
- cancer
- isothermal titration calorimetry
- NMR spectroscopy
- peptide-protease interactions
- X-ray structures