Fusion peptides (FPs) are critical for infection by most enveloped viral pathogens. Members of the CRC previously discovered a fragment of α1-antitrypsin (VIRIP) that targets the gp41 FP of HIV-1 and showed that an optimized derivate was effective in a clinical trial. In the 1st funding period, it was shown that VIRIP-based inhibitors have a high genetic barrier to resistance and can be packaged or modified to increase bioavailability. Goals of the 2nd funding period are to further improve VIRIP-based FP inhibitors and to determine their safety and efficacy in animal models. In addition, various assays were established that will allow to discover novel inhibitors and to better define entry mechanisms of viral pathogens including SARS-CoV-2.