Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine
- 26 December 2006
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 103 (52), 19707-19712
- https://doi.org/10.1073/pnas.0606555104
Abstract
Furin plays a crucial role in embryogenesis and homeostasis and in diseases such as Alzheimer's disease, cancer, and viral and bacterial infections. Thus, inhibition of furin may provide a feasible and promising approach for therapeutic intervention of furin-mediated disease mechanisms. Here, we report on a class of small molecule furin inhibitors based on 2,5-dideoxystreptamine. Derivatization of 2,5-dideoxystreptamine by the addition of guanidinylated aryl groups yielded a set of furin inhibitors with nanomolar range potency against furin when assayed in a biochemical cleavage assay. Moreover, a subset of these furin inhibitors protected RAW 264.7 macrophage cells from toxicity caused by furin-dependent processing of anthrax protective antigen. These inhibitors were found to behave as competitive inhibitors of furin and to be relatively specific for furin. Molecular modeling revealed that these inhibitors may target the active site of furin as they showed site occupancy similar to the alkylating inhibitor decanoyl-Arg-Val-Lys-Arg-CH(2)Cl. The compounds presented here are bona fide synthetic small molecule furin inhibitors that exhibit potency in the nanomolar range, suggesting that they may serve as valuable tools for studying furin action and potential therapeutics agents for furin-dependent diseases.Keywords
This publication has 43 references indexed in Scilit:
- Deletion of the Gene Encoding Proprotein Convertase 5/6 Causes Early Embryonic Lethality in the MouseMolecular and Cellular Biology, 2006
- Modulating furin activity with designed mini‐PDX peptides: Synthesis and in vitro kinetic evaluationFEBS Letters, 2005
- Inter-Alpha-Inhibitor Proteins Are Endogenous Furin Inhibitors and Provide Protection against Experimental Anthrax IntoxicationInfection and Immunity, 2005
- Inhibition of furin by serpin Spn4A from Drosophila melanogasterFEBS Letters, 2004
- The Furin Inhibitor Hexa-d-Arginine Blocks the Activation ofPseudomonas aeruginosaExotoxin A In VivoInfection and Immunity, 2002
- Furin at the cutting edge: From protein traffic to embryogenesis and diseaseNature Reviews Molecular Cell Biology, 2002
- The Contribution of Arginine Residues within the P6–P1 Region of α1-Antitrypsin to Its Reaction with FurinJournal of Biological Chemistry, 2001
- AnthraxNew England Journal of Medicine, 1999
- A novel coumarin‐labelled peptide for sensitive continuous assays of the matrix metalloproteinasesFEBS Letters, 1992
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973