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Review
. 2025;32(13):2524-2546.
doi: 10.2174/0109298673265694231113061842.

Structure and Function of the SARS-CoV-2 6-HB Fusion Core and Peptide-based Fusion Inhibitors: A Review

Guodong Liang  1 , Yue Li  2   3 , Ruijuan Li  1 , Yuheng Ma  1 , Heiya Na  4
Affiliations
Review

Structure and Function of the SARS-CoV-2 6-HB Fusion Core and Peptide-based Fusion Inhibitors: A Review

Guodong Liang et al. Curr Med Chem. 2025.

Abstract

SARS-CoV-2 has swept the world in recent years, triggering a global COVID-19 with a tremendous impact on human health and public safety. Similar to other coronaviruses, the six-helix bundle(6-HB) is not only a core structure driving the fusion of the SARS-CoV-2 envelope with the host cell membrane, but also the target of fusion inhibitors. The sequences from the HR1 or HR2 regions composing 6-HB are thus the original primary structures for the development of peptide-based fusion inhibitors. This review summarized the structure-activity relationship of the SARS-CoV-2 6- HB, analyzed the design methods and functional characteristics of peptide-based fusion inhibitors that contain different regions of HRs, and provided an outlook on the cutting- edge approaches for optimal modification of lead compounds (pan-coronavirization, chemical modification, superhelical construction, etc). We hope that this review will provide researchers with a comprehensive understanding of the state-of-art research progress on both 6-HB and peptide-based fusion inhibitors of SARS-CoV-2, and provide some new insights for the development of antiviral drugs.

Keywords: SARS-CoV-2; antiviral drugs.; fusion inhibitors; hydrophobic residues; peptide; six-helix bundle.

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