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The ubiquitin E2 variant domain of TSG101 (TSG101‐UEV) plays a pivotal role in protein sorting and virus budding by recognizing PTAP motifs within ubiquitinated proteins. Disruption of TSG101‐UEV/PTAP interactions has emerged as a promising strategy for the development of host‐oriented broad‐spectrum 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‐UEV/PTAP binding interface by searching for drug‐like 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‐based activity assays including high‐content bimolecular complementation, virus‐like 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‐UEV/PTAP binding with IC50s in the low μM range and are able to disrupt the interaction between full‐length TSG101 and viral proteins in human cells and inhibit viral replication. State‐of‐the‐art molecular docking studies reveal that the active compounds exploit binding hotspots at the PTAP binding site, unlocking the full binding potential of the TSG101‐UEV binding pockets. These inhibitors represent promising hits for the development of novel broad‐spectrum 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. [ABSTRACT FROM AUTHOR]

An important issue in the formation of concentric eyewalls in a tropical cyclone is the development of a symmetric structure from asymmetric convection. It is proposed herein, with the aid of a nondivergent barotropic model, that concentric vorticity structures result from the interaction between a small and strong inner vortex (the tropical cyclone core) and neighboring weak vortices (the vorticity induced by the moist convection outside the central vortex of a tropical cyclone). The results highlight the pivotal role of the vorticity strength of the inner core vortex in maintaining itself, and in stretching, organizing, and stabilizing the outer vorticity field. Specifically, the core vortex induces a differential rotation across the large and weak vortex to strain out the latter into a vorticity band surrounding the former. The straining out of a large, weak vortex into a concentric vorticity band can also result in the contraction of the outer tangential wind maximum. The stability of the outer band is related to the Fjortoft sufficient condition for stability because the strong inner vortex can cause the wind at the inner edge to be stronger than the outer edge, which allows the vorticity band and therefore the concentric structure to be sustained. Moreover, the inner vortex must possess high vorticity not only to be maintained against any deformation field induced by the outer vortices but also to maintain a smaller enstrophy cascade and to resist the merger process into a monopole. The negative vorticity anomaly in the moat serves as a 'shield' or a barrier to the farther inward mixing the outer vorticity field. The binary vortex experiments described in this paper suggest that the formation of a concentric vorticity structure requires 1) a very strong core vortex with a vorticity at least 6 times stronger than the neighboring vortices, 2) a large neighboring vorticity area that is larger than the core vortex, and 3) a separation distance between the neighboring vorticity field and the core vortex that is within 3 to 4 times the core vortex radius.