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Identification and Characterization of Novel Antiretroviral Compounds: from Small Molecule Library Screening to Rationally Designed Compounds
Jegede, Oyebisi

2007, PHD, Kent State University, College of Biomedical Sciences.
HIV/AIDS pandemic presents a huge challenge to public health with over 40 million people living with HIV/AIDS worldwide. Current treatment is the highly active antiretroviral therapy (HAART). HAART is a combination of two nucleoside reverse transcriptase inhibitors (NRTI), a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), with the fusion inhibitor added as required. HAART has increased patient life expectancy by an average of 8 years. However; these drugs are still expensive, unavailable to over 90% of eligible individuals and associated with widespread drug resistance culminating into therapy failure. Thus, there is an urgent need to identify and characterize novel antiretroviral drugs. In this dissertation, small molecule libraries were screened with either a GFP-tagged lentiviral vector or replicative-competent, fluorescent protein-tagged HIV-1 isolates. Rationally designed compounds were also analyzed for their antiretroviral activity. Characterization of the mechanism(s) of action of these compounds included assessment of compound cellular toxicity (CC50) by trypan blue exclusion and tetrazolium-based colorimetric assays. Viral susceptibility was determined from the IC50 of these compounds against primary and drug-resistant isolates. Their mechanism(s) of antiretroviral activity was confirmed by specific in vitro biochemical assays, time of addition assays and serial passages to select resistant HIV-1 strains. The relevance of drug resistant mutations was assessed by antiviral assays, viral growth kinetics and site-directed mutagenesis. Nine potential candidates for further antiretroviral drug development were identified in this dissertation. Three compounds, CBL 4.0, CBL 4.1 and CBL 4.3 were structurally similar to INDOPY-1, a first-in-class novel nucleoside-competing reverse transcriptase inhibitor (NcRTI) recently described. CBL 17, CBL 21 and CBL 26 were novel non-nucleoside reverse transcriptase inhibitors. However, CBL 26 was very unique due to its dual mode of action. Of the three novel compounds identified from the drug library screening, Hit 2.0 was characterized as a possible reverse transcriptase inhibitor. Hit 3.0 was identified as a likely HIV-1 entry inhibitor. The mechanism of action of Hit 10.0, a novel compound that prevents HIV-1 infection for 12 hours following addition to cells, is yet to be determined.
Miguel Quiñones-Mateu (Advisor)
217 p.

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Jegede, O. (2007). Identification and Characterization of Novel Antiretroviral Compounds: from Small Molecule Library Screening to Rationally Designed Compounds. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Jegede, Oyebisi. "Identification and Characterization of Novel Antiretroviral Compounds: from Small Molecule Library Screening to Rationally Designed Compounds." Electronic Thesis or Dissertation. Kent State University, 2007. OhioLINK Electronic Theses and Dissertations Center. 27 Mar 2015.

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Jegede, Oyebisi "Identification and Characterization of Novel Antiretroviral Compounds: from Small Molecule Library Screening to Rationally Designed Compounds." Electronic Thesis or Dissertation. Kent State University, 2007. https://etd.ohiolink.edu/

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