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Use of retroviral peptide libraries for the identification of novel cellular targets of HIV-1 and the discovery of novel inhibitors


Great strides have been made toward understanding and fighting the Human Immunodeficiency Virus-1 in the thirty years since its discovery (HIV-1). Unfortunately, a true cure remains elusive due to the fact that all of the current pharmaceutical approaches are rendered ineffective by HIV's rapid mutation rate. Furthermore these drugs have severe side effects and, while effective at delaying the onset of Acquired Immunodeficiency Syndrome (AIDS) and extending the lifespan of the infected individuals, are very expensive and ultimately fail to stop the virus. Researchers may spend years using rational design approaches to model a drug that would block the active site of an HIV enzyme, to realize the virus develops resistance within several months of treatment. It is therefore imperative to develop novel approaches to finding direct and indirect means of blocking infection. This dissertation describes the adaptation of retroviral technology in order to discover novel peptide inhibitors of HIV-1 or HIV-1-interacting proteins. It describes the development of high-complexity libraries of random peptides, targeted to specific cellular compartments. The aim of these libraries is to block HIV-1 during various discrete steps in its lifecycle : specifically post-entry, pre-integration early events in the cytoplasm or nucleus, and late events such as processing of the viral polypeptide by its Protease enzyme. It also describes the discovery of a potential new binding partner: the COP9 Signalosome complex. The COP9 Signalosome complex, identified through a screen utilizing one of the libraries, could become a potential new target for HIV-1 inhibition. The complex as well as the interacting 14-3-3 Zeta/Delta protein, which was shown to bind only in the presence of HIV-1 proteins, was purified via a novel approach that allows for a rapid, efficient and specific isolation of large protein complexes and their binding partners

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