Rational Design of Broad-Spectrum Antimicrobial Peptides Derived from the Dengue Virus Capsid Alpha2 Sequence

Antimicrobial peptides (AMP) offer an attractive alternative to antibiotics in the global fight against antibiotic resistance. This work seeks to design a group of amphiphilic AMPs based on the α2 sequence of a Dengue viral capsid protein to address the challenge of ineffective membrane disruptions of AMPs. The design was also inspired by the well-studied G(IIKK)3I-NH2 (G3) for broad-spectrum antimicrobial actions. Because the α2 sequence of the DENV2 C protein is predominantly hydrophobic, it is thought to play the leading role in its own dimerization and membrane insertion during viral infection. Following the native α2 sequence, three Dengue viral-inspired peptides (DVP 1-3), were designed by rebalancing their amphiphilicity and cationic charges. Modified amino acids to enhance hydrophilicity and cationicity (DVP-1). Further sequence modifications involve swapping L with I to reduce toxicity (DVP-2) and swapping K with R to evaluate antimicrobial efficacy and toxicity (DVP-3). This study systematically investigates how key amino acids and the interplay between hydrophilic and hydrophobic sequences influence the interaction of short peptides with bacterial. SANS allows structural determination associated with interfacial interactions at the molecular level. When combined with deuterium labelling, it can determine how virus protein binds to the lipid SUVs through resolving runs measured under parallel isotopic contrasts.