Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants

作者：Drakopoulos Antonios; Tzitzoglaki Christina; McGuire Kelly; Hoffmann Anja; Konstantinidi Athina; Kolokouris Dimitrios; Ma Chunlong; Freudenberger Kathrin; Hutterer Johanna; Gauglitz Guenter; Wang Jun; Schmidtke Michaela; Busath David D; Kolocouris Antonios^*

来源：ACS Medicinal Chemistry Letters, 2018, 9(3): 198-203.

DOI：10.1021/acsmedchemlett.7b00458

• Influenza M2
• S31N mutation
• rimantadine
• rimantadine enantiomers
• isothermal titration calorimetry
• electrophysiology
• binding kinetics
• synthesis
• antiviral assay
• molecular dynamic simulations

Recently, the binding kinetics of a ligand target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher k(off) rates compared to the k(on) rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding k(on) and k(off) against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.

• 出版日期2018-3