*Department of Pharmacology & Toxicology, College of Pharmacy & the BIO5 Institute, The University of Arizona, 1657 E. Helen St., Tucson, AZ 85718, USA; Tel.: +001 520 626 1366; junwang@pharmacy.arizona.edu AM2 was first discovered as the drug target of the antiviral drug amantadine [1]. From a personal perspective, I find both the drug and the target to be fascinating: amantadine is a synthetic cage-shaped small molecule without violations of bond lengths or bond angles and fits snuggly in the wildtype M2 channel cavity; AM2 is the smallest ion channel that is highly selective for protons versus sodium and potassium ions. Soon after their discovery, they immediately caught scientists’ attention: what is the structural basis for proton selectivity of this small protein with only 97 residues? How does amantadine bind to the AM2 channel? These are key questions that need to be addressed in searching for the nextgeneration AM2 channel blockers. It was subsequently revealed that the functional unit of AM2 is a tetramer assembled by four identical monomers through transmembrane helix–helix interactions [2]. Proton selectivity is encoded by the highly conserved H 37 XXW 41 selectivity filter. Although the exact molecular mechanism of how protons are shuttled through the HXXW motif is still under debate [3], the general consensus is that when hydronium diffuses into the AM2 channel cavity and reaches the H37, the protonated H37s experience charge repulsion, which leads to a conformational change from the open out close in to the close out -open in conformers [4]. The proton is then released into the viral interior. This is followed by the relaxation of the M2 channel from the close out -open in to open out -close in conformation for the next round of proton shuttling. Regarding the mechanism of channel inhibition by amantadine, it was proposed that when amantadine fits into the central cavity of AM2 above the H37, it prevents the conformational change from open out -close in to close out -open in , thus halting the proton conductance [5]. M2 is a proven drug target. It is absolutely essential for influenza virus replication: silencing the AM2 gene or blocking the AM2 proton conductance by amantadine leads to inhibition of viral replication [6]. “...it is almost impossible to completely eliminate drug resistance issues of antiviral drugs, regardless of whether they are direct-acting antivirals or host-targeting antivirals.”