Random Mutagenesis Analysis of the Influenza A M2 Proton Channel Reveals Novel Resistance Mutants

Biochemistry
Paul SantnerKresten Lindorff-Larsen

Abstract

The influenza M2 proton channel is a major drug target, but unfortunately, the acquisition of resistance mutations greatly reduces the functional life span of a drug in influenza treatment. New M2 inhibitors that inhibit mutant M2 channels otherwise resistant to the early adamantine-based drugs have been reported, but it remains unclear whether and how easy resistance could arise to such inhibitors. We have combined a newly developed proton conduction assay with an established method for selection and screening, both Escherichia coli-based, to enable the study of M2 function and inhibition. Combining this platform with two groups of structurally different M2 inhibitors allowed us to isolate drug resistant M2 channels from a mutant library. Two groups of M2 variants emerged from this analysis. A first group appeared almost unaffected by the inhibitor, M_089 (N13I, I35L, and F47L) and M_272 (G16C and D44H), and the single-substitution variants derived from these (I35L, L43P, D44H, and L46P). Functionally, these resemble the known drug resistant M2 channels V27A, S31N, and swine flu. In addition, a second group of tested M2 variants were all still inhibited by drugs but to a lesser extent than wild type M2. Molecular dynamics simu...Continue Reading

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Citations

Jul 22, 2019·Viruses·Prabhat Pratap Singh TomarIsaiah T Arkin
Apr 4, 2021·Viruses·Prabhat Pratap Singh TomarIsaiah T Arkin
Jul 3, 2021·Pharmaceuticals·Prabhat Pratap Singh TomarIsaiah T Arkin

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