Bicyclic peptide inhibitor of urokinase-type plasminogen activator: mode of action.
Chembiochem
; 14(16): 2179-88, 2013 Nov 04.
Article
em En
| MEDLINE
| ID: mdl-24115455
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.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos Cíclicos
/
Inibidores de Proteases
/
Ativador de Plasminogênio Tipo Uroquinase
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article