Characterization of interactions between hepatitis C virus NS5B polymerase, annexin A2 and RNA – effects on NS5B catalysis and allosteric inhibition
| Autor: | Solbak, Sara M.Ø., Abdurakhmanov, Eldar, Vedeler, Anni, Danielson, U. Helena |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Hepatitis C virus
Hepatocellular carcinoma viruses Biochemistry and Molecular Biology virus diseases biochemical phenomena metabolism and nutrition allosteric inhibition NS5B RNA allosteric inhibition filibuvir surface plasmon resonance digestive system diseases lcsh:Infectious and parasitic diseases plasmon resonance RNA surface lcsh:RC109-216 Biokemi och molekylärbiologi Annexin A2 filibuvir |
| Zdroj: | Virology Journal, Vol 14, Iss 1, Pp 1-11 (2017) |
| DOI: | 10.1186/s12985-017-0904-4 |
| Popis: | Background Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors. |
| Databáze: | OpenAIRE |
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