Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains.

摘要: Proteolysis mediated by ClpXP is a crucial cellular process linked to bacterial pathogenesis. The development of specific inhibitors has largely focused on ClpP. However, this focus was challenged recent finding showing that conformational control ClpX leads rejection ClpP binders. Thus, we here follow up hit molecule from high throughput screen performed against the whole complex and demonstrate stable inhibition with potency possible. Further investigations revealed small binds without affecting its activity. Likewise, does not inhibit retains overall oligomeric state upon binding. Structure activity relationship studies confirmed structural constraints in all three parts suggesting binding into defined stereospecific pocket. Overall, individual components represents novel mechanism perspectives for further optimization situ applications.