Backbone cyclic peptide, which mimics the nuclear localization signal of human immunodeficiency virus type 1 matrix protein, inhibits nuclear import and virus production in nondividing cells.
Here, we describe an application of the backbone cyclic (BC) proteinomimetic approach to the design and the synthesis of a BC peptide which functionally mimics the nuclear localization signal (NLS) region of the human immunodeficiency virus type 1 matrix protein (HIV-1 MA). On the basis of the NMR structure of HIV-1 MA, a library of BC peptides was designed and screened for the ability to inhibit nuclear import of NLS-BSA in digitonin-permeabilized HeLa and Colo-205 cultured cells. The screening yielded a lead compound (IC50 = 3 microM) which was used for the design of a second library. This library led to the discovery of a highly potent BC peptide, designated BCvir, with an IC50 value of 35 nM. This inhibitory potency is compared to a value of 12 microM exhibited by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected nondividing cultured human T-cells and was relatively resistant to tryptic digestion. These properties make BCvir a potential candidate for the development of a novel class of antiviral drugs which will be based on blocking nuclear import of viral genomes.
Friedler
A
A
Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Israel.
Zakai
N
N
Karni
O
O
Broder
Y C
YC
Baraz
L
L
Kotler
M
M
Loyter
A
A
Gilon
C
C
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004355:Drug Stability; D015683:Gene Products, gag / Q000737:chemistry*; D015488:HIV Antigens / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D019913:Nuclear Localization Signals / Q000187:drug effects*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D015202:Protein Engineering; D014357:Trypsin; D014407:Tumor Cells, Cultured; D014764:Viral Proteins; D014779:Virus Replication / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015683:Gene Products, gag; D015488:HIV Antigens; D019913:Nuclear Localization Signals; D019151:Peptide Library; D010456:Peptides, Cyclic; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D014357:Trypsin