Polyarginine Inhibits gp160 Processing by Furin and Suppresses Productive Human Immunodeficiency Virus Type 1 Infection

Abstract

Correct endoproteolytic maturation of gp160 is essential for the infectivity of human immunodeficiency virus type 1. This processing of human immunodeficiency virus-1 envelope protein, gp160, into gp120 and gp41 has been attributed to the activity of the cellular subtilisinlike proprotein convertase furin. The prototypic furin recognition cleavage site is Arg-X-Arg/Lys-Arg. Arg-ArgArg-Arg-Arg-Arg or longer iterations of polyarginine have been shown to be competitive inhibitors of substrate cleavage by furin. Here, we tested polyarginine for inhibition of productive human immunodeficiency virus-1-infection in T-cell lines, primary peripheral blood mononuclear cells, and macrophages. We found that polyarginine inhibited significantly human immunodeficiency virus-1 replication at concentrations that were benign to cell cultures ex vivo and mice in vivo. Using a fluorogenic assay, we demonstrated that polyarginine potently inhibited substrate-specific proteolytic cleavage by furin. Moreover, we verified that authentic processing of human immunodeficiency virus-1 gp160 synthesized in human cells from an infectious human immunodeficiency virus-1 (HIV-1) molecular clone was effectively blocked by polyarginine. Taken together, our data support that inhibitors of proteolytic processing of gp160 may be useful for combating human immunodeficiency virus-1 and that polyarginine represents a lead example of such inhibitors.

Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex

“…Of the known pPCs only four, namely furin, PC7, PC5, and PACE4 show a broad tissue distribution (9). Our own experiments show that only PC7 and furin, which can both be inhibited by polyarginines (41), are expressed at significant levels in T2 cells (data not shown). Thus, in future studies it will be of great interest to see whether furin, PC7 or both are involved in the post-ER stabilization of MHC I and what kind of peptide ligands participates in the proposed reloading process.…”

Processing of peptide and hormone precursors at the dibasic cleavage sites

“…Indeed, D-poly-Arg peptides have been shown to be potent and relatively selective inhibitors of furin, and their inhibitory potency has been found to be proportional to their length [116,117]. Moreover, some of these D-Arg oligopeptides were able to block the lethal effects of Pseudomonas aeruginosa exotoxin or to suppress the infection of HIV1 infection in vivo.…”

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

“…The discovery that furin activity is required for PV infection raises the possibility that furin (or furin͞PC5/6) inhibitors might be effective as topical microbicides to prevent genital infection by HPV, and they might also inhibit viruses, such as HIV, whose production depends on furin (38,39). Furin inhibitors that prevent the activation of bacterial toxins, such as anthrax toxin (40), are under development.…”