RESUMEN
A new strategy to exploit galectin presence to target matrix metalloproteinases (MMPs) is presented. A bifunctional conjugate with lactose and an inhibitor for MMPs is able to bind MMP and Gal-3 simultaneously. This compound might allow the lectin to attract the MMP inhibitor to the tumour site and to block protumoural activities of the lectin at the same time.
Asunto(s)
Acetamidas/química , Acetamidas/síntesis química , Acetamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Galectinas/química , Galectinas/metabolismo , Glicoconjugados/química , Lectinas/química , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteinasas de la Matriz/química , Metaloproteinasas de la Matriz/metabolismo , Sulfonamidas/química , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Espectroscopía de Resonancia Magnética , NeoplasiasRESUMEN
Double cyclization of short linear peptides obtained by solid phase peptide synthesis was used to prepare bridged bicyclic peptides (BBPs) corresponding to the topology of bridged bicyclic alkanes such as norbornane. Diastereomeric norbornapeptides were investigated by 1H-NMR, X-ray crystallography and CD spectroscopy and found to represent rigid globular scaffolds stabilized by intramolecular backbone hydrogen bonds with scaffold geometries determined by the chirality of amino acid residues and sharing structural features of ß-turns and α-helices. Proteome profiling by capture compound mass spectrometry (CCMS) led to the discovery of the norbornapeptide 27c binding selectively to calmodulin as an example of a BBP protein binder. This and other BBPs showed high stability towards proteolytic degradation in serum.
RESUMEN
Norbornapeptides (bicyclo[2.2.1]heptapeptides) and related bicyclic homodetic peptides were prepared by solid-phase peptide synthesis using an orthogonal protection scheme. These conformationally rigid peptides cover an almost pristine area of peptide topological space and adopt globular shapes similar to those of short α-helical peptides.