Inhibition of nuclear import by backbone cyclic peptide analogs

US6664368B1 · kind B1 · utility

Assignees

• YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM LTD. · IL
• Peptor Ltd. · IL

Inventors

• Assaf Friedler · Jerusalem, IL
• Abraham Loyter · Jerusalem, IL
• Chaim Gilon · Jerusalem, IL
• Amnon Wolf · Herzliya, IL

Key dates

• Filing date: May 4, 2000
• Grant date: Dec 16, 2003
• Expiry date: May 4, 2020

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12N2740/16322
• WIPO field: Biotechnology
• WIPO sector: Chemistry

Abstract

The design and the synthesis of backbone cyclic peptide analogs which functionally mimic the nuclear localization signal (NLS) region of macromolecules is disclosed. The principles of the invention are exemplified for the NLS sequences of the human immunodeficiency virus type 1 proteins MA, Vpr, Tat and NLS-like sequences of HIV-1 protein Vif. We disclose the discovery of a novel, highly potent backbone cyclic peptide, designated BCvir, which inhibits nuclear import with an IC50 value of 35 nM. This inhibitory potency is to be compared to 12 &mgr;M exhibited by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected non-dividing cultured human T-cells and was relatively resistant to tryptic digestion. These properties render backbone cyclic peptide analogs of NLS or NLS-like sequences as candidates for novel drugs based on blocking nuclear import of viral genomes.