Targeting the Motor Protein Cagβ Blocks Oncoprotein CagA-induced Host Inflammation in Helicobacter pylori: An in silico Analysis

Helicobacter pylori is a common gut microbiota, responsible for severe gastritis, peptic ulcer disease and an increased risk of gastric cancer. The Cag pathogenicity island helps H. pylori cause disease by forming a molecular syringe to attack host cells that transfer the CagA oncoprotein into the gastric cells. Once inside the host cell, Cag A modifies multiple signalling pathways, leading to major alterations and even malignancy. Cagβ, the coupling protein of T4SS, plays a significant role in detecting and carrying CagA through an ATP- dependent mechanism. As Cagβ functions like a molecular motor of the secretion system, targeting this particular protein may provide a way to prevent CagA delivery. This study aims to model the 3D structure of Cagβ motor protein and identify repurposed drugs capable of inhibiting its activity through molecular docking studies. Venetoclax was found one of the most promising drug, having binding affinity of -11.6 Kcal/mol with expected structural stability via interaction with SER301, MET297, GLY309 and LEU249 residue. Blocking Cagβ regulated activity may block the CagA delivery into host cells, subsequently reducing downstream inflammatory signalling pathways and limiting the further pathogenesis of H. pylori infection.

Helicobacter pylori, Cagβ, Cag A, Type IV Secretion System (or T4SS)

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