Honors College Thesis
 

Identification of a compound series by high throughput screening capable of reversing the antiviral effect of Ribavirin in tissue culture

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https://ir.library.oregonstate.edu/concern/honors_college_theses/rx913r97v

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  • A compound series capable of reversing the antiviral effect of Ribavirin (RBV) against H1N1 was identified from a high throughput screen designed to discover compounds capable of increasing the fidelity of the RNA-dependent RNA polymerase (RDRP) n ribovirus quasispecies. Two lead compounds, RIC-1 (EC50 of 78.4 nM) and RIC-2 (EC50 of 217 nM), returned viral growth to control levels by completely inhibiting the antiviral activity of RBV. Both compounds demonstrated a loss of activity when incubated at 37°C in media only, losing functionality within 3 hours. Incubation of RIC-1 or RIC-2 with cells for only 2.5 minutes, however, was able to maintain viral growth by inhibiting RBV for the full 72 hour growth period. Subsequent testing showed the RIC series was not effective against a second mutagen, 5-fluorouracil, and RIC-2 did not prevent or slow the development of antiviral resistance when viral populations were grown in the presence of Zanamivir. Furthermore, RIC-1 was ineffective in alleviating inhibition of the inosine 5’-monophosphate dehydrogenase (IMPDH) pathway by the inhibitor mycophenolic acid (MPA). Anti-RBV activity was relieved by increasing the concentration of RBV, suggesting the RIC series acts to competitively inhibit RBV. The mechanism of action associated with the RIC compound series is still unclear; however, it appears to act independent of the intended function of RDRP fidelity modification.
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