Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gpl60

Abstract

The envelope glycoprotein of human immunodeficiency virus (HIV) initiates infection by mediating fusion of the viral envelope with the cell membrane. Fusion activity requires proteolytic cleavage of the gp160 protein into gp120 and gp41 at a site containing several arginine and lysine residues. Activation at basic cleavage sites is observed with many membrane proteins of cellular and viral origin. We have recently found that the enzyme activating the haemagglutinin of fowl plague virus (FPV), an avian influenza virus, is furin. Furin, a subtilisin-like eukaryotic endoprotease, has a substrate specificity for the consensus amino-acid sequence Arg-X-Lys/Arg-Arg at the cleavage site. We show here that the glycoprotein of HIV-1, which has the same protease recognition motif as the FPV haemagglutinin, is also activated by furin.

Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases

“…Based on our findings that COS-1 cells can process wild-type MT1-MMP as well as its 108 RRKR mutant, coupled with the recent demonstration that ␣ 1 PI PITT is unable to efficiently inhibit proprotein convertase-dependent pathways (Vollenweider et al, 1996;Cui et al, 1998), we propose that the removal of the MT1-MMP prodomain is a prerequisite for the efficient display of proteolytic activity. Interestingly, although partial blockade of proMT1-MMP processing was reported recently with a chloromethylketone inhibitor (Maquoi et al, 1998;Kurschat et al, 1999), this agent is not specific for proprotein convertases and also exerts cytotoxic effects (Hallenberger et al, 1992;Okumura et al, 1997;Jean et al, 1998).…”

HIV-1 proprotein processing as a target for gene therapy

“…32 Mammalian convertases such as furin cleave the envelope precursors. 19 Based on these observations, the catalytic site of a 1 AT was exchanged with the consensus sequence recognized by convertases. The engineered serpin (a 1 AT Portland, a 1 PDX) was shown to be a potent inhibitor of furin.…”

“…Inhibition of gp160 processing is known to generate viral particles unable to activate the necessary fusion between the viral particle and the plasma membrane of the target cell. 19 Interestingly, for some viruses, a direct correlation between the efficiency of virus proprotein cleavage by cellular endoproteases and virulence can be drawn. 37,38 Native a 1 AT may provide an alternative to the peptides mimicking the cleavage region of gp160.…”

“…18 The cellular serine protease, furin, was the first of this group that was shown to catalyze proteolytic maturation of both HIV-1 and influenza virus envelope glycoproteins. 19 Recent data suggest that other proteases may also be involved in such processing (for review see Ref 20).…”

“…21 Just as cellular serine protease activity is fundamentally important to envelope, viral aspartyl protease activity is required for gag proprotein processing: both processes are necessary to generate infectious viral progeny. 19,22 Thus, gene delivery to inhibit proteolytic cleavage of envelope and gag precursors could represent a new approach for gene therapy to interfere with HIV-1 infectivity.…”