Design, Synthesis and Study of Peptidomimetic Inhibitors against Different Cellular Targets

Manna, Asit Kumar (2011) Design, Synthesis and Study of Peptidomimetic Inhibitors against Different Cellular Targets. PhD thesis, University of Calcutta.

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    Supervisors

    SupervisorsEmail
    Roy, Siddhartha

    Abstract

    In the living system thousands of biochemical processes occur spontaneously. All such biochemical processes are not same for different ways of living kingdom. Some biochemical pathways are unique for a specific type of organism. Moreover in many pathological conditions some of these processes are aberrant, inappropriate or poorly regulated. Many of such biochemical processes have been very rigorously studied by the scientific communities. It is already known that the protein-protein and protein-nucleic acid interactions play many crucial roles in many biological processes. The ability to interfere such interactions would, therefore, provide many attractive opportunities for the treatment of human disease. Three biochemical pathways have been taken to address for disruptions of specific protein–protein or protein nucleic acid interactions by peptidomimetics. The translation of Hepatitis C Virus (HCV) poly-protein is mediated through interaction of human La protein with HCV-IRES near initiator AUG. It was earlier demonstrated that RNA recognition motif 2 (RRM2) of La protein interacts with HCV-IRES near initiator AUG and facilitates translation of hepatitis C virus (HCV). So the interface of HCV-IRES near initiator AUG and RRM2 of La protein is a very good drug target. NF-κB family proteins have been constitutively active in almost all tumor tissues. Suppression of NF-κB in cancer cell lines inhibits proliferation, causes cell cycle arrest, and leads to apoptosis, indicating the crucial role of NF-κB in cell proliferation and survival. What causes the constitutive activation of NF-κB in tumor cells is incompletely understood. IKK complex plays a very crucial role in the activation of NF-κB family proteins. It consists of IKKα, IKKβ, and IKKγ subunit proteins. Upon phosphorylation of IKK complex it phosphorylates IκBs protein consequently NF-κB family proteins are activated. By disruption of the IKK complex NF-κB pathway can be controlled hence uncontrolled proliferation of tumor tissues. Majority of bacteria and all archaea, which do not possess GlnRS, the accurate translation of the genetic code of Gln occurs through a two-step process. In the first step, tRNAGln is misacylated with glutamic acid by a non-discriminating GluRS, and then the mischarged Glu-tRNAGln is transformed into Gln-tRNAGln by Glu-tRNAGln–dependent amidotransferase (Glu-AdT). Glu-AdT converts Glu-tRNAGln into Gln-tRNAGln by initially activating Glu-tRNAGln into γ-phosphoryl-Glu-tRNAGln at the expense of ATP, which is subsequently transamidated into Gln-tRNAGln using ammonia generated by hydrolysis of glutamine. The active site of Glu-AdT (gatCAB present in mycobacterium) for hydrolysis of glutamine is a hot spot for drug target against mycobacterium. This thesis attempts to develop peptidomimetic inhibitors to disrupt such specific protein-protein and protein-nucleic acid interactions occurs in such hot spots for drug target.

    Item Type: Thesis (PhD)
    URI: http://www.eprints.iicb.res.in/id/eprint/333
    Subjects: Structural Biology & Bioinformatics
    Divisions: UNSPECIFIED
    Depositing User: Dr Asit Manna
    Date Deposited: 27 Oct 2011 12:13
    Last Modified: 06 Feb 2012 12:17
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