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Investigation into Catalytic Metallodrugs that Target Hepatitis C IRES RNA: Development, Characterization, and Mechanism

Ross, Martin James
http://rave.ohiolink.edu/etdc/view?acc_num=osu1440421045

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Chemistry.
Metals have been used for therapeutic purposes since the dawn of civilization including the ancient Egyptians using copper jars to sterilize their water. This use of metal and others were commonplace until the discovery of penicillin. With the discovery of penicillin, small molecules with a rational and target approach became the standard of the drug industry. Traditional drugs to this today mostly consist of organic compounds, composed primarily of carbon, hydrogen, nitrogen, oxygen, chlorine, and fluorine. The discovery of cis-platin and the advancement of our understanding of how the body works, including how our bodies handle metals, and advance techniques have created the environment for the renaissance in interest and development of bioinorganic compounds for therapeutic use. Metal complexes offer unique opportunities and properties that traditional small molecules lack. One such approach is through the development of catalytic metallodrugs which by design are able to recognize and target multiple of the same therapeutic target. This ability enable these compounds to be dose at lower dosage, sub-stoichiometric equivalents, which will lead to fewer off-targeting and side-effects. Limited preliminary studies have applied this approach towards ribonucleic acids, such as Hepatitis C IRES RNA. Hepatitis C Virus (HCV) affects over 200 million people globally which unchecked can lead to cirrhosis or liver cancer. Unfortunately, there is not a vaccine available for HCV like hepatitis A or hepatitis B. The current approach towards treatment involve cocktails, mixtures of several compounds each with a different therapeutic target. Initial reports have demonstrated the activity of the Cu-GGHYrFK, copper peptide complex, in recognition of stem-loop IIb of the HCV IRES RNA. This research starts by understanding the products and binding of Cu-GGHYrFK to stem-loop IIb (SLIIb). With the lead compound, pathways and mechanism for oxidative degradation of RNA were developed. Derivatives including the all D-configuration and all L-configuration of this peptide were synthesized to examine the importance of stereochemistry on reactivity. After this, a structure activity relationship study based upon the all L configuration was preformed to evaluate the role of each of the targeting domain amino acids on binding, reactivity, and cellular uptake. This was then continued to the first position after the Cu-GGH domain to examine catalytic properties. A series of different metal ions, Ni2+, Co3+, Pd2+, Pt2+, Au3+, were incorporated into GGHYrFK, the lead compound, to investigate the importance of the metal ion with reactivity. A further more in-depth mechanistic study was carried out with Cu-GGHYrFK with the use of heavy water, H218O to determine the source of oxygen into products of RNA degradation. The novel 5’-product, 5’-geminal diol was reported. Finally, several catalytic drugs based on reported peptides that bind stem-loop IV of the HCV IRES RNA were developed and characterized. These compounds represent a paradigm shift in therapeutic approach for the treatment of hepatitis c virus.
Jimmy Cowan (Advisor)
A. Douglas Kinghorn (Committee Member)
Hannah Shafaat (Committee Member)
Claudia Turro (Committee Member)
281 p.
Chemistry
RNA oxidation; ATCUN; SLIIb; SLIV; HCV; IRES; 5 NTR; Cu; Ni; Pd; Pt; Au; Co;

Recommended Citations

Citations

  • Ross, M. J. (2015). Investigation into Catalytic Metallodrugs that Target Hepatitis C IRES RNA: Development, Characterization, and Mechanism [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1440421045

    APA Style (7th edition)

  • Ross, Martin. Investigation into Catalytic Metallodrugs that Target Hepatitis C IRES RNA: Development, Characterization, and Mechanism. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1440421045.

    MLA Style (8th edition)

  • Ross, Martin. "Investigation into Catalytic Metallodrugs that Target Hepatitis C IRES RNA: Development, Characterization, and Mechanism." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1440421045

    Chicago Manual of Style (17th edition)

osu1440421045
538
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This open access ETD is published by The Ohio State University and OhioLINK.