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The system with a beautifully druggable ATP pocket.
Famille hétérogène d'ATPases AAA+ couplées à des effecteurs variables (nucléases, peptidases, TIR). Profil druggable très favorable : poches ATP catalytiques bien définies, modulables par small molecules. Cinq sous-types (AVAST 1-5) avec activités distinctes.
AVAST = Antiviral ATPase coupled to a variable effector. Five subtypes have been characterized (AVAST 1 through 5), each coupling an AAA+ ATPase to a different effector: a nuclease for one, a peptidase for another, a TIR domain (NADase) for AVAST3. The AAA+ family is one of the oldest and most conserved enzyme superfamilies: present from bacteria to humans, with abundant crystallographic structures resolved and well-defined "druggable" ATP pockets. It's one of the best pharmacological profiles among anti-phage systems: strong structural conservation with eukaryotic targets (VPS4 in viral budding, p97/VCP in protein degradation, RUVBL1/2 in influenza replication), and a bacterial target that is screenable without interfering toxicity.
AVAST3 (TIR-effector) simultaneously targets the druggable AAA+ fold and the TIR fold (SARM1/Thoeris parallel). It is a double-hit target in pharmacology: screen a library against AVAST3, and you potentially get hits exploitable in both VPS4-inhibition (antiviral) and SARM1-modulation (neurology).
The p97/VCP inhibitor called CB-5083 entered clinical trials (Phase 1, Cleave Biosciences) on solid tumors. It showed efficacy, but was halted due to muscular side effects (myopathy). Revisiting the target with AVAST3 as a bacterial proxy to optimize selectivity could unlock this therapeutic mechanism.
