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Synthesis of Novel Nucleoside Analogs Targeting HCV

Alabdullah, Bader Saleh
http://orcid.org/0000-0001-7050-6902
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1524827142181671

Abstract Details

2018, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Despite all the advancement that has been produced in the clinic for treating HCV infection, it is nevertheless a major causal agent of liver disease due to its silent nature. With 7 genotypes and many subtypes, the search for a pan-genotypic treatment is challenging and leads in many cases to the use of combination treatments to tackle the infection. Ribavirin (RBV) and Pegylated Interferon Alfa-2b (pegIFNa-2b) represented the standard of care (SoC) for a long period. Sustained Virologic Response (SVR) was only achieved in a low percentage of patients with this SoC. Also, the SoC was associated with severe side effects that resulted in the termination of treatment in many cases. So, it is necessary to find a treatment that is pan-genotypic and has fewer side effects than that of the SoC. Identification of multiple points to disrupt the HCV viral life cycle and to halt viral protein synthesis was enabled through determination of the crystal structure of the viral proteins and a better understanding of the viral life cycle. Most notably the determination iv of the crystal structure of the HCV NS5B RdRp as it is the catalytic machinery for viral replication. The conserved nature of the HCV NS5B active site across viral species, as compared to other HCV viral proteins, along with the fact that there is no human NS5B made NS5B a primary target for drug design and development. In this project, we synthesized 2'-C-acetyl and 2'-C-(1-hydroxyethyl) uridine and started the synthesis of 2'-C-formyl and 2'-C-aminomethyl uridine analogs. Based on the approval of Sofosbuvir, which is 2'-modified uridine that acts as an NS5B inhibitor, we assume that these compounds will work as non-obligate chain terminators for the synthesis of the viral RNA by the NS5B enzyme.
Amanda Bryant-Friedrich (Committee Chair)
James Slama (Committee Member)
Viranga Tillekeratne (Committee Member)
Malathi Krishnamurthy (Committee Member)
171 p.
Chemistry; Organic Chemistry; Pharmacy Sciences
Chemistry; Medicinal Chemistry; Organic Chemistry; Hepatitis C Virus; HCV; Modified Nucleosides; Anti-HCV Medications; Uridine Analogs; Sofosbuvir; Synthesis

Recommended Citations

Citations

  • Alabdullah, B. S. (2018). Synthesis of Novel Nucleoside Analogs Targeting HCV [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1524827142181671

    APA Style (7th edition)

  • Alabdullah, Bader. Synthesis of Novel Nucleoside Analogs Targeting HCV. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1524827142181671.

    MLA Style (8th edition)

  • Alabdullah, Bader. "Synthesis of Novel Nucleoside Analogs Targeting HCV." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1524827142181671

    Chicago Manual of Style (17th edition)

toledo1524827142181671
454
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This open access ETD is published by University of Toledo and OhioLINK.