title: 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 subtilisin-like proprotein convertase furin. The prototypic furin recognition cleavage site is Arg-X-Arg/Lys-Arg. Arg-Arg-Arg-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.
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, USA.
authors.forename: Karen V
authors.initials: KV
authors.lastname: Kibler
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyazato
authors.forename: Venkat S R K
authors.initials: VS
authors.lastname: Yedavalli
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Dayton
authors.forename: Bertram L
authors.initials: BL
authors.lastname: Jacobs
authors.forename: George
authors.initials: G
authors.lastname: Dapolito
authors.forename: Seong-jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
mesh_terms: D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000494:pharmacology; D045683:Furin / Q000378:metabolism*; D019302:HIV Envelope Protein gp160 / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D015151:Immunoblotting; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000821:virology; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D012235:Rhodamines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D005456:Fluorescent Dyes; D019302:HIV Envelope Protein gp160; D010455:Peptides; D012235:Rhodamines; C015462:polyarginine; D045683:Furin