Targeting MERS-CoV Spike Fusion Machinery with Antiviral Peptides (AVPs): In Silico Exploration of the Heptad Repeat 2 (HR2) Domain

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) remains a significant global health threat, necessitating the development of effective antiviral therapeutics. Targeting the heptad repeat 2 (HR2) domain of the MERS-CoV spike protein offers a promising strategy to inhibit viral fusion and entry into host cells. This study investigates a panel of antiviral peptides (AVPs), focusing on Griffithsin, Brevinin-2, and CCL20, to evaluate their potential as fusion inhibitors against the HR2 domain. Employing comprehensive computational approaches, including molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy calculations, we characterized the peptide-protein interactions and stability of these AVPs in complex with HR2. Our results demonstrate that Griffithsin, Brevinin-2, and CCL20 exhibit stronger binding affinities (−213.69, −168.83, and −165.17 kcal/mol, respectively) compared to the standard inhibitor Peptide-6 (−49.73 kcal/mol). MD simulations reveal stable complexes and indicate disruption of critical hydrogen bonds in the Ile1255–Gln1271 region of HR2, essential for six-helix bundle formation and viral fusion. Physicochemical analyses further suggest favorable stability, half-life, and low hemolytic potential, supporting their suitability as therapeutic candidates. These findings align with prior studies highlighting the broad-spectrum antiviral activity of Griffithsin and validate the therapeutic promise of Brevinin-2 and CCL20. While this computational investigation lays the groundwork, further in vitro and in vivo validation and optimization of pharmacokinetics and delivery are necessary for clinical development. This study advances the rational design of peptide-based fusion inhibitors targeting MERS-CoV and provides valuable insights into antiviral strategies against emerging coronaviruses.