HCV is responsible for 60% of the cases of chronic hepatitis and 50% of cases of cirrhosis, end- stage liver disease, and liver cancer. An effective vaccine has proved elusive and the preferred therapy with pegylated interferon is effective in less than 50% of patients with genotype 1 and 75% of patients with genotypes 2 or 3. Clearly, new treatment alternatives are needed. Interest in HCV IRES RNA as a drug target is reflected by the increasing number of small and large pharma companies pursuing that goal. MetalloPharm has created a novel platform technology (metallodrugs) that has the potential to irreversibly destroy the HCV IRES RNA.
The specific aims are directed toward selection of a lead and back-up drug candidate for IND-enabling pre- clinical testing following validation of cellular mode of action against IRES RNA and uptake mechanisms;assessment of PK, toxicity and efficacy data;and exploration of methods to improve serum half life.
Millions of people worldwide are infected with HCV, including a significant portion of the US population. HCV is responsible for 60% of the cases of chronic hepatitis and 50% of cases of cirrhosis, end-stage liver disease, and liver cancer. An effective vaccine has proved elusive and current therapy is effective in less than 50% of patients. Clearly, new treatment alternatives are needed. MetalloPharm has created a novel class of therapeutics (metallodrugs) that function by destroying a key molecule in the viral life cycle with the potential to halt the progression of, or completely eliminate the virus.
|Ross, Martin James; Fidai, Insiya; Cowan, James A (2017) Analysis of Structure-Activity Relationships Based on the Hepatitis?C Virus SLIIb Internal Ribosomal Entry Sequence RNA-Targeting GGHYRFK?Cu Complex. Chembiochem 18:1743-1754|
|Ross, Martin James; Bradford, Seth S; Cowan, J A (2015) Catalytic metallodrugs based on the LaR2C peptide target HCV SLIV IRES RNA. Dalton Trans 44:20972-82|
|Yu, Zhen; Han, Menglu; Cowan, James A (2015) Toward the design of a catalytic metallodrug: selective cleavage of G-quadruplex telomeric DNA by an anticancer copper-acridine-ATCUN complex. Angew Chem Int Ed Engl 54:1901-5|
|Bradford, Seth S; Ross, Martin James; Fidai, Insiya et al. (2014) Insight into the recognition, binding, and reactivity of catalytic metallodrugs targeting stem loop?IIb of hepatitis?C IRES RNA. ChemMedChem 9:1275-85|
|Fidai, Insiya; Hocharoen, Lalintip; Bradford, Seth et al. (2014) Inactivation of sortase A mediated by metal ATCUN complexes. J Biol Inorg Chem 19:1327-39|
|Hocharoen, Lalintip; Joyner, Jeff C; Cowan, J A (2013) N- versus C-domain selectivity of catalytic inactivation of human angiotensin converting enzyme by lisinopril-coupled transition metal chelates. J Med Chem 56:9826-36|
|Joyner, Jeff C; Hodnick, W F; Cowan, Ada S et al. (2013) Antimicrobial metallopeptides with broad nuclease and ribonuclease activity. Chem Commun (Camb) 49:2118-20|
|Joyner, Jeff C; Keuper, Kevin D; Cowan, J A (2013) Analysis of RNA cleavage by MALDI-TOF mass spectrometry. Nucleic Acids Res 41:e2|
|Joyner, Jeff C; Keuper, Kevin D; Cowan, J A (2013) Kinetics and Mechanisms of Oxidative Cleavage of HIV RRE RNA by Rev-Coupled Transition Metal Chelates. Chem Sci 4:1707-1718|
|Joyner, Jeff C; Keuper, Kevin D; Cowan, J A (2012) DNA nuclease activity of Rev-coupled transition metal chelates. Dalton Trans 41:6567-78|
Showing the most recent 10 out of 14 publications