Targeting Middle East Respiratory Syndrome Coronavirus Spike Fusion Machinery With Antiviral Peptides: In Silico Exploration of the Heptad Repeat 2 Domain.
Antiviral peptides just took a step forward against MERS-CoV. Researchers ran a head-to-head digital showdown, pitting Griffithsin, Brevinin-2, and CCL20 against the Middle East Respiratory Syndrome Coronavirus’s spike protein. The target: the heptad repeat 2 (HR2) domain, a linchpin for viral fusion. If you can block HR2, you stop the virus from entering cells—game over for infection.
Microbiologyopen
by Alotaiq N, Dermawan D, Chtita S
“Targeting Middle East Respiratory Syndrome Coronavirus Spike Fusion Machinery With Antiviral Peptides: In Silico Exploration of the Heptad Repeat 2 Domain. Alotaiq N(1), Dermawan D(2), Chtita S(3). Author information: (1)Health Sciences Research Center (HSRC), Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia. (2)Department of Applied Biotechnology, Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland. (3)Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Casablanca, Morocco. 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. © 2026 The Author(s). MicrobiologyOpen published by John Wiley & Sons Ltd.”
Here’s what the team did: They used molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations to see how tightly these peptides bind HR2 and how stable the complexes are. The numbers didn’t disappoint. Griffithsin, Brevinin-2, and CCL20 all showed much stronger binding than the standard inhibitor Peptide-6. The binding free energies were off the charts: -213.69 kcal/mol for Griffithsin, -168.83 for Brevinin-2, and -165.17 for CCL20. For comparison, Peptide-6 limped in at -49.73.
Key takeaway: These peptides don’t just stick to HR2—they disrupt critical hydrogen bonds, especially in the Ile1255-Gln1271 region. That’s where the virus needs to form its six-helix bundle to fuse with host cells. Stop the bundle, stop the virus.
Physicochemical analysis was another win. All three peptides ranked high for stability, half-life, and low risk of breaking red blood cells (low hemolytic potential). That’s exactly what you want in a research peptide moving toward real-world testing.
What’s next? In vitro and in vivo studies, plus dialing in pharmacokinetics and delivery. But this computational work gives researchers a smart starting point for developing peptide-based fusion inhibitors against MERS-CoV and other coronaviruses.
Curious about other antiviral peptides or want to explore more? Check out the peptide research index for the latest. This study proves that sharp computational screening can move the field forward—fast.
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