Influenza A virus M2 (A/M2) forms a homotetrameric channel in viral membranes that is highly selective for protons. A/M2 has been extensively studied by electrophysiologists, biophysicists, structural biologists and biochemists in order to understand the mechanism and selectivity of proton conductance from the structural basis. Medicinal chemists have also studied A/M2 as therapeutic target for anti-flu drugs. However, research on A/M2 drug binding lead to entirely different binding sites of two very similar anti-flu drugs. In light of the urgency in developing novel antivirals against drug resistant A/M2 mutants, it is imperative to solve this discrepancy in order to guide the next generation of antiviral discovery. This highly contentious debate was settled in favor of pore blocking through collaborate efforts with Dr. Mei Hong in Iowa State University. We showed by solid state NMR that the single high affinity pharmacologically relevant drug binding site locates at the N-terminal lumen with amine pointing towards C-terminal using 13C-2H rotational echo double-resonance NMR distance measurement of 13C-labeled M2TM and deuterated amantadine in lipid bilayers. Guided by the high resolution structure of drug-complexed M2, rational drug design based on BL-1743 scaffold lead to a series of spiran amines, which are not only 10 fold more active than amantadine, but also has moderate activity against drug resistant mutants V27A and L26F. Subsequent optimization improved the potency with IC50s down to low micromolar range. By substituting the carbon quaternary center with silicon, silaspiran amines were designed and synthesized and show higher antiviral potency than their carbon analogs. Finally in searching for novel scaffolds, a library of inhibitors was selected based on the structure and activity relationship results from previous studies and screened against M2. It was found that A/M2 is able to accommodate inhibitors with diverse scaffolds. In conclusion, this thesis study solved the A/M2 drug binding site controversy and developed a series of potent A/M2 inhibitors that are promising as drug candidates.