SARS-CoV-2 and other related viruses enter host cells via receptor recognition and membrane fusion. The 5-Helix bundle (5HB) pentamer assay was constructed at the University of Minnesota for the purpose of identifying potential inhibitors SARS-CoV-2 virus entry. 5HB is capable of binding to the viral spike heptad repeats (HR2), which is a critical component in the virus entry pathway and makes 5HB a potential inhibitor of virus entry. Following miniaturization and optimization into a 1536 well format, we completed a pilot HTS vs 5HB and were able to find small molecule inhibitors that appear to compete with the 5HB binding to HR2. We continued to complete the full HTS campaign by screening 635,262 compounds. Following the completion of the HTS around the 5HB pentamer, we tested a monomer version of the 5HB against a pilot screen which would help confirm on target activity. Here in, we illustrate the implementation of the ultra high throughput assay (uHTS) and the comparison of the pentamer vs the monomer assay outcomes. At completion, we screened 130 compounds in dose response format against the 5HB assay. We also screened the same compounds in a secondary cell-based assay that looked for inhibitors of either Machupo entry or SARS2 entry in a dual luciferase transient transfection system (assay optimized and implemented by Yuka Osuka at UF-Scripps). At the conclusion of the screens, as well as a cytotoxicity screen, 41 compounds were found to be selective inhibitors of the 5HB pentamer assay. From these assays, 31 compounds and analogs were selected. The 5HB monomer assay was tested against the Maybridge pilot of 14,000+ compounds. After comparison with the 5HB pentamer assay outcomes 52 compounds, including the 31 compounds and analogs from the 5HB pentamer screen were tested in both assays. 5 compounds showed good potency and are currently being tested in pseudovirus and live virus assays.