Abstract
Amyloid formation contributes to a broad range of biological and pathological processes, from bacterial biofilm organization to human neurodegenerative and metabolic diseases. Consequently, molecules capable of inhibiting amyloid assembly across structurally unrelated proteins are exceptionally uncommon and mechanistically significant. Recent findings identifying the Helicobacter pylori virulence factor CagA as a potent broad-spectrum amyloid inhibitor establish an unexpected connection between microbial pathogenicity and protein misfolding biology. Experimental studies demonstrated that CagA and its active derivative, CagAN, suppress aggregation of both bacterial functional amyloids and multiple disease-associated human amyloid proteins, including amyloid-beta, tau, alpha-synuclein, and islet amyloid polypeptide. Mechanistic analyses further indicate that CagA interferes with different stages of amyloid assembly depending on the target substrate, including primary nucleation, secondary nucleation, and fibril elongation. Despite this promising anti-amyloid activity, CagA remains a pathogenic bacterial effector associated with epithelial disruption, oncogenic signaling, and gastric carcinogenesis. Therefore, its translational value likely lies not in direct therapeutic use, but in identifying and engineering safer anti-aggregation motifs derived from its structure. This review examines the dual biological identity of CagA, summarizes current mechanistic evidence supporting its anti-amyloid activity, and discusses future opportunities for developing detoxified peptides, biologics, and AI-guided anti-aggregation therapeutics inspired by CagA biology.