Biology Reference
In-Depth Information
the inhibition of the nuclear import of transcription factor NF-AT. Before activation,
NF-AT is localized to the cytoplasm in a highly phosphorylated state. An influx of
Ca
2+
activates the phosphatase calcineurin, which dephosphorylates NF-AT. This
unmasks NLS sequences, allowing the transcription factor to translocate into the
nucleus where it activates cytokine genes such as IL2 and IL4 (Shibasaki et al.
1996). This is blocked by the widely used immunosuppressive agents cyclosporin
A and FK506, which interact with calcineurin to regulate its activity (Liu et al.
1991). The disadvantage of this approach is the elicitation of side effects resulting
from the fact that the inhibition of calcineurin activity affects several other signal-
ing cascades as well. In this respect, the exploitation of unconventional interactions
between viral molecules and components of the nuclear transport machinery may
represent a more promising approach, since these interactions should be sufficiently
different from cellular interactions to ensure a high specificity of the intervention.
In line with this, several studies report on small molecule inhibitors that are able to
specifically interfere with the nuclear translocation of the HIV preintegration
complex correlating with a potent anti-HIV activity of the respective drugs in
primary human cells (Al-Abed et al. 2002; Glushakova et al. 2000; Haffar et al.
1998, 2005; Haffar and Bukrinsky 2005). Thus, the detailed characterization of
interactions of HCMV proteins fulfilling essential functions for viral replication
with components of the nuclear transport machinery may not only contribute to our
understanding of molecular mechanisms but may also be useful to develop novel
drugs interfering with HCMV replication. Consequently, we are presently investi-
gating whether peptide aptamers targeting the pUL84 NLS domain are able to
inhibit the interaction with importin-α proteins and could thus be used to interfere
with the nuclear localization of this essential viral regulatory protein, leading to a
block of HCMV DNA replication.
Acknowledgements
Work presented in this review was supported by the Deutsche
Forschungsgemeinschaft (SFB473), the GRK1071, the IZKF Erlangen, and the Wilhelm Sander
Stiftung.
References
Al-Abed Y, Dubrovsky L, Ruzsicska B, Seepersaud M, Bukrinsky M (2002) Inhibition of HIV-1
nuclear import via Schiff base formation with arylene bis(methylketone) compounds. Bioorg
Med Chem Lett 12:3117-3119
Allcock RJ, Price P, Gaudieri S, Leelayuwat C, Witt CS, Dawkins RL (1999) Characterisation of
the human central MHC gene, BAT1: genomic structure and expression. Exp Clin
Immunogenet 16:98-106
Allcock RJ, Williams JH, Price P (2001) The central MHC gene, BAT1, may encode a protein
that down-regulates cytokine production. Genes Cells 6:487-494
Arnold M, Nath A, Hauber J, Kehlenbach RH (2006a) Multiple importins function as nuclear
transport receptors for the Rev protein of human immunodeficiency virus type 1. J Biol Chem
281:20883-20890
Arnold M, Nath A, Wohlwend D, Kehlenbach RH (2006b) Transportin is a major nuclear import
receptor for c-Fos: a novel mode of cargo interaction. J Biol Chem 281:5492-5499
