Obiettivo
Human T-cell leukemia virus type 1 (HTLV-I), the first human retrovirus to be discovered, has been shown to be clinically associated with adult T-cell leukemia/lymphoma and tropical spastic paresis/HTLV-I-associated myelopathy. Currently, it is estimated that 15 million to 20 million individuals worldwide are infected with HTLV-I, for which there is no effective treatment, as is the case for adult T-cell leukemia. For the virus to mature and assemble infectious particles, the polyproteins must be processed by retroviral protease. HTLV aspartic protease is thus considered an attractive target for the development of inhibitors to treat HTLV-I infections.
However, to date only very few peptide-based inhibitors against HTLV-I protease have been reported. The development of effective inhibitors against HTLV-I protease is thus the major goal of this proposal. The first step will be to synthesize "by means of native chemical ligation (NCL)" HTLV-I protease, which is a small dimmer comprising two identical subunits, each containing 125 amino acids. NCL is particularly suitable for the synthesis of large quantities of proteins for biological studies. There will thus be sufficient quantities of material available for the screening process to discover HTLV-I protease inhibitors.
The NCL strategy will also be used to prepare proteases with unnatural modifications, which will be used for inhibition studies. New ligation chemistries will also be explored for the synthesis of polypeptides from free cysteine peptides. It is believed that the proposed study will lead to the development of novel inhibitors against HTLV protease, which will, in turn, inspire the synthesis of similar inhibitors against other aspartic proteases involved in a variety of diseases. It is hoped that the tools developed for the chemical synthesis of HTLV-I protease will further enhance our ability to chemically synthesize other targets, leading to an understanding of protein function and enzyme activity.
Campo scientifico
Parole chiave
Invito a presentare proposte
FP6-2004-MOBILITY-12
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Meccanismo di finanziamento
EIF - Marie Curie actions-Intra-European FellowshipsCoordinatore
BEER-SHEVA
Israele