The influenza virus infects many people causing localized epidemics with the occasional pandemic. Influenza is known to have higher rates of death and morbidity in immunocompromised individuals, infants, and elderly people. Current methods to control the spread of the influenza virus are vaccinations and antiviral drugs. Vaccines are the most effective method to protect the public but can lack the necessary efficacy to protect the public every flu season. Antiviral drugs alleviate the burden of the flu, but the influenza virus mutates rapidly and has developed resistances to the current antiviral drugs. Genome-wide screenings have identified SUMOylation as an important host factor in the influenza virus lifecycle. Small Ubiquitin-like Modifier (SUMO) is a reversible post-translational modifier that uses a multi-step enzymatic cascade to alter protein function and stability. The dysregulation of SUMOylation has been known to associated with many diseases such as; carcinogenesis, neurodegenerative disease, and viral infections. Fӧrster Resonance Energy Transfer (FRET) is a non-radiative energy transfer that occurs between two fluorophores that are within 1-10 nm and have overlapping spectra. Our group has developed a quantitative FRET (qFRET) platform to measure protein interactions and enzyme kinetics. I have developed another application for our qFRET platform to identify the SUMOylated lysine residue (K131) of the non-structural protein 1 of the influenza A virus which is important for the influenza virus replication but not essential for the influenza virus. I have tested the efficacy of our SUMOylation inhibitor (STE) on the influenza A virus and found a novel SUMOylated lysine residue that is essential for the influenza A virus. Finally, I have discerned the acquisition of drug-resistant mutations by targeting host factors compared to viral proteins of the influenza A virus.