Small-molecule inhibitor: furin inhibitor 1

Summary Literature

Name

Common name: furin inhibitor 1
Other names: furin inhibitor I; decanoyl-Arg-Val-Lys-Arg-chloromethane; Dec-RVKR-CMK

Inhibition

History: Dibasic peptidylchloromethane (CMK) inhibitors of the intracellular processing of viruses were known to be potentiated by hydrophobic acyl substituents that increased cell penetration (Garten et al., 1989). The further discovery of the importance of P4 Arg as a specificity determinant for furin by several groups (e.g. Hosaka et al., 1991) led to the design of decanoyl-Arg-Xaa-Arg/Lys-Arg-chloromethanes, amongst which. decanoyl-Arg-Glu-Lys-Arg-CMK was described by Stieneke-Grober et al. (1992). An early example of the use of furin inhibitor I was that of Vey et al. (1995).
Peptidases inhibited: Furin inhibitor I is in fact not specific for furin, but inhibits all seven of the proprotein convertases: furin, proprotein convertase 1, proprotein convertase 2, proprotein convertase 4, PACE4 proprotein convertase, proprotein convertase 5 and proprotein convertase 7 (Tian & Jianhua, 2010). Also inhibited is blisterase (Poole et al., 2003).
Mechanism: A peptidylchloromethane is expected to inhibit serine peptidases irreversibly, forming a covalent complex. Consistent with this expectation, progress curves for the time-dependent loss of activity of PACE4 proprotein convertase in the presence of furin inhibitor I at a range of concentrations have been shown (Basak et al., 2008), and Fugere et al. (2002) were able to titrate several proprotein convertases with the inhibitor. The following values for K_i have been listed: furin 1.0 nM, PACE4 proprotein convertase 3.6 nM, proprotein convertase 5 1.12 nM and proprotein convertase 7 0.12 nM (Remacle et al., 2010). The crystal structure of the complex of furin inhibitor I with mouse furin has been determined by Henrich et al. (2003).
Pharmaceutical relevance: Furin inhibitor I is not proposed for use as a drug, but has value in research. It inhibits the intracellular processing of viral proteins including influenza virus hemagglutinin and HIV-1 glycoprotein gp160 (Bendjennat et al., 2001). Furin removes prosequences from many proteins during their secretion from cells, so inhibition of its activity by furin inhibitor I affects protein secretion (Koo et al., 2007).

Chemistry

CID at PubChem: 16760442
Structure
Chemical/biochemical name: 2-[[6-amino-2-[[2-[[5-(diaminomethylideneamino)-2-(undecanoylamino)pentanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl chloride
Formula weight: 744

General

Inhibitor class: This compound is of the halomethylketone class of serine peptidase inhibitors. Such compounds are activated ketones that form tetrahedral adducts with serine peptidases. On the basis of detailed studies with several serine peptidases it seems that a Michaelis complex is formed intially, and then a hemiketal is formed by attack of the active site serine on the carbonyl carbon of the inhibitor. The hemiketal still contains the halide. When the halide is chlorine rather than fluorine the reaction may proceed to alkylation of the ring of the active site His, with liberation of the chlorine (Powers, 1977). The halomethylketones have been reviewed by Powers et al. (2002), pp. 4646 - 4656.