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UBC Theses and Dissertations

Development of inhibitors of alternative splicing events crucial to HIV-1 replication : a new anti-HIV/AIDS strategy targeting the host cell machinery Bandy, Laura Elizabeth


Introduction : HIV infects over 35 million people worldwide . Since the introduction of HAART the survival rate for HIV/AIDS patien ts has increased exponentially. HAART, although effective , does have long term limitations resulting from cross resistance to c ertain drugs of the same class , compliance, and side effects ; therefore , investigating alternative avenues and targets for therapeutic treatment is vital . Through compound library screening, IDC16, a tetracyclic indole compound , has been identified as an inhibitor of SR protein splicing factor 1 ( SRSF1). This protein play s a redundant role in human splicing but is specifically used in HIV - 1 infected cell alternative splicing. Blocking HIV - 1 alternative splicing through inhibitio n of SRSF1 function may establish a novel strategy for HIV/AIDS therapy and is advantageous because it (i) targets a protein that is essential to HIV replication, (ii) targets a huma n protein potentially eliminating the chances of mutation and subsequent r esistance to drug therapy . Although IDC16 displays cytotoxicity, the design of mimics of IDC16 could allow for the discovery of an equally or more potent compound w hich eliminates the cytotoxic effects. Hypothesis : The synthesis of appropriately functionalized and conformation ally mobile ring opened mimics of IDC16 will lead to the identification of new HIV replication inhibitors that : target SRSF1 ; are not cytotoxic ; do not intercalate DNA ; and retain similar or superior anti - HIV activity when compared to IDC16 . Objectives : The synthesi s and evaluation of the anti - HIV activity of a library of IDC16 mimics corresponding to different structural types from a common 2 - pyridinone scaffold: 1 ) bisheterocyclic amides, 2 ) bisheterocyclic oxadiazoles, 3 ) fused bishet erocyclic isoxazolidin - 7 - ones , 4 ) fused bisheterocyclic 5 - arylpyrazolidin - 7 - ones and 5 ) C - 4 (hetero)aryl substituted 2 - pyridinones . Results: Our effort to synthesize inhibitors of HIV - 1 by creating a library of IDC16 mimics led to the discovery of DGPS39/LB - 45 . This compound was 90% as effective as the HAART drug AZT in blocking HIV - 1 replication. Significance : Creating a non - cytotoxic IDC16 mi mic with the same or greater affinity for the target protein SRSF1 will allow for further investigation int o a novel treatment of HIV/AIDS ; which has the potential to circumvent the problems with viral resistance experienced with HAART.

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