Discovery of small molecule inhibitors of the Tsg101-PTAP interaction as potential host-targeted broad-spectrum antivirals.

Emerging and re-emerging viruses pose a major threat to global public health. Developing broad-spectrum antivirals (BSAs) targeting host factors that are essential for multiple viruses to complete their life cycle could enable a rapid response against future viral outbreaks.1 In this context, the interaction between the highly conserved viral late domain PTAP and the cellular protein tumor susceptibility gene 101 (TSG101) is a crucial step in the replication cycle of viruses belonging to different families, making this protein a very promising but underexplored target for the development of novel broad-spectrum antiviral agents.2,3 Starting from strong biological results on a previously identified hit compound, we synthesize a set of simplified derivatives, improving drug-likeness and synthetic accessibility while maintaining the ability to block the PTAP/TSG101 interaction in the low uM range.4 This work reinforces the concept of host-oriented therapeutics and presents a much-needed opportunity to identify BSAs less prone to resistance development.