Rational design of a dual-function, LL-37/HNP-1, chimeric antimicrobial peptide: a broad-spectrum AMP against respiratory co-infections

Abstract

Respiratory viral–bacterial co-infections remain difficult to treat because current therapies typically target pathogens individually. In this study, we designed and computationally evaluated a dual-function chimeric antimicrobial peptide that integrates the conserved antiviral and antibacterial domains of LL-37 and human neutrophil peptide-1 (HNP-1). The domains were fused using a rigid EAAAK linker, and sequence optimization was performed to improve physicochemical properties. Methods: Using structural modeling and molecular dynamics simulations, we assessed the peptide’s stability, solubility, conformational organization, and safety. The optimized construct showed enhanced antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus (hRV), along with improved predicted antibacterial activity against Streptococcus pneumoniae and Staphylococcus aureus. Results: Structural validation demonstrated favorable α-helix and β-strand organization and improved model quality. Molecular dynamics simulations further confirmed the stability and compactness of the peptide through analyses of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen bonding, radius of gyration, and solvent-accessible surface area (SASA). Conclusion: Overall, these computational findings highlight the potential of the LL-37/HNP-1 fusion peptide as a broad-spectrum therapeutic candidate for respiratory co-infections, with future applications in inhalable or nanoparticle-based delivery systems. Experimental antimicrobial assays will be required to validate its biological activity.