Structure-based design of peptide ligands targeting transcription in Helicobacter pylori

Helicobacter pylori colonize the gastric epithelial cells and poses a strong risk factor for gastric complications like chronic gastritis, ulcer diseases, and gastric cancer. Despite the complex treatment regimens, antibiotic resistance is the primary cause of eradication failure and calls for alternate treatment strategy. This study aims to design peptide ligands that specifically target protein-protein interactions in the transcription machinery of H. pylori. The dissociable σ-factor known as SigA, which binds with the RNA polymerase (RNAP) core beta-prime subunit (RpoC). This interacting region has been targeted to design specific peptide ligands using structure-based computational methods. The lack of experimental structures necessitated generating structural models for Hp RpoC, Hp SigA and Hp RpoC-SigA complex structure. The complex was built based on hybrid template-based modeling (TBM) techniques. The RpoC-SigA interface has been exploited to design five suitable peptides-three peptides from H. pylori SigA (P1, P2, and P3) and two peptides from the SigA-interacting regions of H. pylori RpoC (P4 and P5). Investigation of the binding affinity of all five peptides suggests that P1, P3, and P5 exhibit significant affinity, indicating a potential hindrance to RNAP interaction with transcription factors prior to holoenzyme formation. These peptides may serve as promising inhibitors against H. pylori infection.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00679-4.