New substrate analogue furin inhibitors derived from 4-amidinobenzylamide |
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Authors: | Becker Gero L Hardes Kornelia Steinmetzer Torsten |
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Institution: | Department of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany |
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Abstract: | A series of new peptidomimetic furin inhibitors was synthesized, which was derived from our previously described lead structure phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (1). Substitution of Val by other amino acid residues revealed several highly potent furin inhibitors with Ki values of less than 2 nM, containing guanidinoalanine, Ile, Phe or Tyr in the P3 position. The replacement of the P2 Arg by Lys was also well accepted, whereas the incorporation of d-amino acids at various positions resulted in poor inhibitors. The use of the 4-amidinobenzylamide group provides convenient synthetic access to stable proprotein convertase inhibitors and derivatives as biochemical tools and for further studies in cell culture. |
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Keywords: | Furin Proprotein convertase Protease inhibitor Peptidomimetic inhibitor Serine protease |
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