Ligands based on bicyclic peptides can combine favourable properties of antibodies (good binding affinity and target specificity) and small molecule ligands (stability, access to chemical synthesis, diffusion properties) and might be suitable molecular structures for the development of therapeutics1. By using a combinatorial methodology based on phage display and a chemical cyclisation reaction2, we isolated a potent (Ki = 53 nM) and selective inhibitor of human urokinase-type plasminogen activator (uPA), a trypsin-like serine protease that participates in the turnover of extracellular matrix (ECM) proteins and is implicated in tumor growth and invasion3. X-ray structure determination of the bicyclic peptide bound to uPA revealed that both peptide loops engage the target to form a large interaction surface of 701 Å2 with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics. Moreover, further study revealed that the in vitro-evolved bicyclic peptide are stable in vivo and remain active for several days overcoming a limitation faced by many in vitro-evolved peptide leads and promises to be suitable for the generation of long-acting peptide therapeutics4,5. Its therapeutic effect is currently being tested in vivo.

Genetically Encoded Synthetic Polypeptides as Innovative Cancer Therapeutics

ANGELINI, Alessandro;
2013

Abstract

Ligands based on bicyclic peptides can combine favourable properties of antibodies (good binding affinity and target specificity) and small molecule ligands (stability, access to chemical synthesis, diffusion properties) and might be suitable molecular structures for the development of therapeutics1. By using a combinatorial methodology based on phage display and a chemical cyclisation reaction2, we isolated a potent (Ki = 53 nM) and selective inhibitor of human urokinase-type plasminogen activator (uPA), a trypsin-like serine protease that participates in the turnover of extracellular matrix (ECM) proteins and is implicated in tumor growth and invasion3. X-ray structure determination of the bicyclic peptide bound to uPA revealed that both peptide loops engage the target to form a large interaction surface of 701 Å2 with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics. Moreover, further study revealed that the in vitro-evolved bicyclic peptide are stable in vivo and remain active for several days overcoming a limitation faced by many in vitro-evolved peptide leads and promises to be suitable for the generation of long-acting peptide therapeutics4,5. Its therapeutic effect is currently being tested in vivo.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10278/3684887
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