Amantadine was discovered as an anti-viral drug for influenza A by interrupting the ion channel activity of the M2 protein. Recently, amantadine has resurfaced as a potential antiviral for coronaviruses by inhibiting the function of the virus’ membrane associated E protein ion channel. If amantadine’s targets are membrane proteins, is it also possible that amantadine has specific membrane interactions? Biological membranes are now widely understood to be laterally heterogeneous, where proteins preferentially co-localize with specific lipid domains. Using the canonical phase separating lipid mixture of cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) we studied amantadine’s interaction with lipid membranes. Differential scanning calorimetry (DSC) data showed that amantadine lowers the phase transition of the POPC/DSPC/cholesterol membranes (from 40.7 to 39.4 °C), implying increased disordering of the lipid structure. It was also determined with Langmuir trough techniques that amantadine preferentially binds to disordered lipids, such as POPC. Interestingly, cholesterol reduced the rate of amantadine binding to POPC, but increased the rate of binding to DSPC. We suspect that this is due to cholesterol ordering POPC, while having the inverse effect on DSPC. It therefore seems that amantadine preferentially binds to domains with disordered lipids. As different proteins preferentially co-localize with different lipid domains, our results have implications as to which proteins amantadine can localize with and affect their function.

Amantadine interacts with disordered lipids in phase separated membranes

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.