To summarize, we demonstrated that non-native interaction interfaces might form when proteins abnormally oligomerize. Using the MERS-CoV N protein as an example, we showed that non-native interfaces might serve as targets for small-molecule, structure-based screening. We also proposed several stratagems to rationally identify potential non-native interface targets for screening. We believe that we have discovered and tested an alternative drug discovery paradigm that could help expand the repertoire of lead compounds against various pathogens.