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Inhibition of nuclear transport of pathogenic kariophilic proteins:

Many pathogenic agents such as viruses use the cellular nuclear import pathway in-order to transport viral proteins into the cell nucleus. These viral proteins contain a unique Nuclear Localization Signals (NLS’s), which are able to mediate interactions of the viral proteins and importins and thus be transported to the nucleus. Since there is no consensus NLS sequence the viral NLS is a good target for development of inhibitors.        
We are screening for peptide inhibitors, which will block specifically the nuclear import of human HIV-1 and the plant Gemini virus kariophilic proteins using two main concepts.         
a. In collaboration with Prof. Chaim Gilon we are synthesizing backbone cyclic peptides, which mimic the NLS sequence and are able to block the viral protein nuclear trans location. 

 Cyclic HIV-1 Rev peptide mimicking the Rev Argenin Rich Motif

 

Cyclic HIV-1 Rev peptide mimicking the Rev Argenin Rich Motif (ARM).

From:Hariton-Gazal, et al Biochemistry 2005, 44, 11555-11566.

 

b. Using different in-vivo and in-vitro screening methods we are searching for short peptides which will bind specifically to viral NLS sequences and thus block viral protein and nucleic acid nuclear import.

 

Inhibition of nuclear up-take of the HIV VprN peptide with a fragment obtained using a phage display library

 

Inhibition of nuclear up-take of the HIV VprN peptide with a fragment obtained using a phage display library

From: Krichevsky, A. et al. Virology 2003,  305, 77–92.

 

The same approach is used in collaboration with Prof. Vitaly Citovsky to develop peptides that will specifically bind to the NLSs of the Agrobacterium VirE2 and to that of the TYLCV coat protein. This is in order to develop peptides that wiil inhibit infection of plants by Agrobacteriun and by TYLCV (The tomato yellow curl leaf virus).

 

 

 

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