Details

Autor(en) / Beteiligte

• Kibler, Karen V
• Miyazato, Akiko
• Yedavalli, Venkat S R K
• Dayton, Andrew I
• Jacobs, Bertram L
• Dapolito, George
• Kim, Seong-jin
• Jeang, Kuan-Teh

Titel

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.