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Disruption of TSG101\u2010UEV\/PTAP interactions has emerged as a promising strategy for the development of host\u2010oriented broad\u2010spectrum antivirals with low susceptibility to resistance. TSG101 is a challenging target characterized by an extended and flat binding interface, low affinity for PTAP ligands, and complex binding energetics. Here, we assess the druggability of the TSG101\u2010UEV\/PTAP binding interface by searching for drug\u2010like inhibitors and evaluating their ability to block PTAP recognition, impair budding, and inhibit viral proliferation. A discovery workflow was established by combining in vitro miniaturized HTS assays and a set of cell\u2010based activity assays including high\u2010content bimolecular complementation, virus\u2010like particle release measurement, and antiviral testing in live virus infection. This approach has allowed us to identify a set of chemically diverse molecules that block TSG101\u2010UEV\/PTAP binding with IC50s in the low \u03bcM range and are able to disrupt the interaction between full\u2010length TSG101 and viral proteins in human cells and inhibit viral replication. State\u2010of\u2010the\u2010art molecular docking studies reveal that the active compounds exploit binding hotspots at the PTAP binding site, unlocking the full binding potential of the TSG101\u2010UEV binding pockets. These inhibitors represent promising hits for the development of novel broad\u2010spectrum antivirals through targeted optimization and are also valuable tools for investigating the involvement of ESCRT in the proliferation of different virus families and study the secondary effects induced by the disruption of ESCRT\/virus interactions.<\/jats:p>","DOI":"10.1002\/pro.70005","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T14:12:21Z","timestamp":1735222341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the druggability of the <scp>UEV<\/scp> domain of human <scp>TSG101<\/scp> in search for broad\u2010spectrum antivirals"],"prefix":"10.1002","volume":"34","author":[{"given":"Fernando","family":"Montero","sequence":"first","affiliation":[{"name":"Department of Physical Chemistry, Institute of Biotechnology, and Unit of Excellence in Chemistry Applied to 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