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Polyarginine Inhibits gp160 Processing by Furin and Suppresses Productive Human Immunodeficiency Virus Type 1 Infection
Ist Teil von
The Journal of biological chemistry, 2004-11, Vol.279 (47), p.49055-49063
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
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.