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Background <p>The COVID-19 pandemic renewed global focus on the development of novel antiviral agents. Peptides, owing to their high specificity and tunability, represent a promising therapeutic class. The integrin-binding peptide ATN-161 (Ac-PHSCN-NH₂) has shown potential as a SARS-CoV-2 fusion inhibitor by disrupting α5β1 integrin-mediated entry.</p> Purpose <p>This study aimed to develop and evaluate novel ATN-161 analogues with improved biochemical stability and antiviral activity by introducing proline substitutions into its core sequence.</p> Methods <p>Three analogues, Ac-P<b>P</b>SCN-NH₂ (Analogue-I), Ac-PH<b>P</b>CN-NH₂ (Analogue-II), and Ac-PHS<b>P</b>N-NH₂ (Analogue-III), were synthesized using SPPS, characterized by HPLC, mass spectrometry and NMR spectroscopy. Antiviral activity was assessed in SARS-CoV-2-infected Vero (E6) cells using cytopathic effect monitoring and RT-qPCR. In silico molecular docking and dynamics simulations were performed against α5β1 integrin and ACE2 to evaluate binding affinity and stability.</p> Results <p>Analogue-III demonstrated superior antiviral activity, reducing viral RNA load by ~ 100-fold with an IC<sub>50</sub> = 0.6 µM, outperforming ATN-161 (IC<sub>50</sub> = 3.16 µM), while maintaining a favourable cytotoxicity profile. Docking studies revealed the strongest binding affinities (up to − 17.05&#xa0;kcal/mol) and lowest RMSD values (as low as 1.113 Å), while dynamics simulations supported stable and favorable interactions.</p> Conclusion <p>Proline-based structural modifications of ATN-161 yielded a promising antiviral candidate with improved activity. Analogue-III (Ac-PHS<b>P</b>N-NH₂) merits further preclinical evaluation as a potential fusion inhibitor targeting integrin-mediated viral entry.</p>

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Design and Evaluation of ATN-161 Analogues as Fusion Inhibitors Targeting Integrins in SARS-CoV-2

  • 期刊论文

  • 发表日期：

    2025年5月30日

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  • Marriam Munawar,
  • Naeem-Ul-Haq Khan,
  • Sobia Jabeen,
  • Saman Taj,
  • Rizwan Bashir,
  • Wasim Abbas,
  • Waqar Rauf,
  • Mazhar Iqbal

摘要

Background

The COVID-19 pandemic renewed global focus on the development of novel antiviral agents. Peptides, owing to their high specificity and tunability, represent a promising therapeutic class. The integrin-binding peptide ATN-161 (Ac-PHSCN-NH₂) has shown potential as a SARS-CoV-2 fusion inhibitor by disrupting α5β1 integrin-mediated entry.

Purpose

This study aimed to develop and evaluate novel ATN-161 analogues with improved biochemical stability and antiviral activity by introducing proline substitutions into its core sequence.

Methods

Three analogues, Ac-PPSCN-NH₂ (Analogue-I), Ac-PHPCN-NH₂ (Analogue-II), and Ac-PHSPN-NH₂ (Analogue-III), were synthesized using SPPS, characterized by HPLC, mass spectrometry and NMR spectroscopy. Antiviral activity was assessed in SARS-CoV-2-infected Vero (E6) cells using cytopathic effect monitoring and RT-qPCR. In silico molecular docking and dynamics simulations were performed against α5β1 integrin and ACE2 to evaluate binding affinity and stability.

Results

Analogue-III demonstrated superior antiviral activity, reducing viral RNA load by ~ 100-fold with an IC50 = 0.6 µM, outperforming ATN-161 (IC50 = 3.16 µM), while maintaining a favourable cytotoxicity profile. Docking studies revealed the strongest binding affinities (up to − 17.05 kcal/mol) and lowest RMSD values (as low as 1.113 Å), while dynamics simulations supported stable and favorable interactions.

Conclusion

Proline-based structural modifications of ATN-161 yielded a promising antiviral candidate with improved activity. Analogue-III (Ac-PHSPN-NH₂) merits further preclinical evaluation as a potential fusion inhibitor targeting integrin-mediated viral entry.