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

doi:10.2174/0109298673265694231113061842

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 Liang¹, Yue Li^{2

3}, Ruijuan Li¹, Yuheng Ma¹, Heiya Na⁴

Affiliations

¹ Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Huhhot, 010110, P.R. China.
² Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
³ School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
⁴ College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, P.R. China.

PMID: 38018192
DOI: 10.2174/0109298673265694231113061842

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.

. 2025;32(13):2524-2546.

doi: 10.2174/0109298673265694231113061842.

Authors

Guodong Liang¹, Yue Li^{2

3}, Ruijuan Li¹, Yuheng Ma¹, Heiya Na⁴

Affiliations

¹ Key Laboratory for Candidate Drug Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Huhhot, 010110, P.R. China.
² Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
³ School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
⁴ College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, P.R. China.

PMID: 38018192
DOI: 10.2174/0109298673265694231113061842

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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Zhong R, Zhan J, Zhang S. Zhong R, et al. Appl Biochem Biotechnol. 2024 Jul;196(7):3891-3913. doi: 10.1007/s12010-023-04727-z. Epub 2023 Oct 4. Appl Biochem Biotechnol. 2024. PMID: 37792175

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[1] Su S.; Wong G.; Shi W.; Liu J.; Lai A.C.K.; Zhou J.; Liu W.; Bi Y.; Gao G.F.; Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016,24(6),490-502 - DOI - PubMed

[2] Su S.; Wong G.; Shi W.; Liu J.; Lai A.C.K.; Zhou J.; Liu W.; Bi Y.; Gao G.F.; Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016,24(6),490-502 - DOI - PubMed

[3] Mei M.; Tan X.; Current strategies of antiviral drug discovery for COVID-19. Front Mol Biosci 2021,8,671263 - DOI - PubMed

[4] Mei M.; Tan X.; Current strategies of antiviral drug discovery for COVID-19. Front Mol Biosci 2021,8,671263 - DOI - PubMed

[5] Lai C.C.; Shih T.P.; Ko W.C.; Tang H.J.; Hsueh P.R.; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020,55(3),105924 - DOI - PubMed

[6] Lai C.C.; Shih T.P.; Ko W.C.; Tang H.J.; Hsueh P.R.; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020,55(3),105924 - DOI - PubMed

[7] Stein S.R.; Ramelli S.C.; Grazioli A.; Chung J.Y.; Singh M.; Yinda C.K.; Winkler C.W.; Sun J.; Dickey J.M.; Ylaya K.; Ko S.H.; Platt A.P.; Burbelo P.D.; Quezado M.; Pittaluga S.; Purcell M.; Munster V.J.; Belinky F.; Ramos-Benitez M.J.; Boritz E.A.; Lach I.A.; Herr D.L.; Rabin J.; Saharia K.K.; Madathil R.J.; Tabatabai A.; Soherwardi S.; McCurdy M.T.; Babyak A.L.; Perez Valencia L.J.; Curran S.J.; Richert M.E.; Young W.J.; Young S.P.; Gasmi B.; Sampaio De Melo M.; Desar S.; Tadros S.; Nasir N.; Jin X.; Rajan S.; Dikoglu E.; Ozkaya N.; Smith G.; Emanuel E.R.; Kelsall B.L.; Olivera J.A.; Blawas M.; Star R.A.; Hays N.; Singireddy S.; Wu J.; Raja K.; Curto R.; Chung J.E.; Borth A.J.; Bowers K.A.; Weichold A.M.; Minor P.A.; Moshref M.A.N.; Kelly E.E.; Sajadi M.M.; Scalea T.M.; Tran D.; Dahi S.; Deatrick K.B.; Krause E.M.; Herrold J.A.; Hochberg E.S.; Cornachione C.R.; Levine A.R.; Richards J.E.; Elder J.; Burke A.P.; Mazzeffi M.A.; Christenson R.H.; Chancer Z.A.; Abdulmahdi M.; Sopha S.; Goldberg T.; Sangwan Y.; Sudano K.; Blume D.; Radin B.; Arnouk M.; Eagan J.W.; Palermo R.; Harris A.D.; Pohida T.; Garmendia-Cedillos M.; Dold G.; Saglio E.; Pham P.; Peterson K.E.; Cohen J.I.; de Wit E.; Vannella K.M.; Hewitt S.M.; Kleiner D.E.; Chertow D.S.; SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 2022,612(7941),758-763 - DOI - PubMed

[8] Stein S.R.; Ramelli S.C.; Grazioli A.; Chung J.Y.; Singh M.; Yinda C.K.; Winkler C.W.; Sun J.; Dickey J.M.; Ylaya K.; Ko S.H.; Platt A.P.; Burbelo P.D.; Quezado M.; Pittaluga S.; Purcell M.; Munster V.J.; Belinky F.; Ramos-Benitez M.J.; Boritz E.A.; Lach I.A.; Herr D.L.; Rabin J.; Saharia K.K.; Madathil R.J.; Tabatabai A.; Soherwardi S.; McCurdy M.T.; Babyak A.L.; Perez Valencia L.J.; Curran S.J.; Richert M.E.; Young W.J.; Young S.P.; Gasmi B.; Sampaio De Melo M.; Desar S.; Tadros S.; Nasir N.; Jin X.; Rajan S.; Dikoglu E.; Ozkaya N.; Smith G.; Emanuel E.R.; Kelsall B.L.; Olivera J.A.; Blawas M.; Star R.A.; Hays N.; Singireddy S.; Wu J.; Raja K.; Curto R.; Chung J.E.; Borth A.J.; Bowers K.A.; Weichold A.M.; Minor P.A.; Moshref M.A.N.; Kelly E.E.; Sajadi M.M.; Scalea T.M.; Tran D.; Dahi S.; Deatrick K.B.; Krause E.M.; Herrold J.A.; Hochberg E.S.; Cornachione C.R.; Levine A.R.; Richards J.E.; Elder J.; Burke A.P.; Mazzeffi M.A.; Christenson R.H.; Chancer Z.A.; Abdulmahdi M.; Sopha S.; Goldberg T.; Sangwan Y.; Sudano K.; Blume D.; Radin B.; Arnouk M.; Eagan J.W.; Palermo R.; Harris A.D.; Pohida T.; Garmendia-Cedillos M.; Dold G.; Saglio E.; Pham P.; Peterson K.E.; Cohen J.I.; de Wit E.; Vannella K.M.; Hewitt S.M.; Kleiner D.E.; Chertow D.S.; SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 2022,612(7941),758-763 - DOI - PubMed

[9] Menni C.; Valdes A.M.; Polidori L.; Antonelli M.; Penamakuri S.; Nogal A.; Louca P.; May A.; Figueiredo J.C.; Hu C.; Molteni E.; Canas L.; Österdahl M.F.; Modat M.; Sudre C.H.; Fox B.; Hammers A.; Wolf J.; Capdevila J.; Chan A.T.; David S.P.; Steves C.J.; Ourselin S.; Spector T.D.; Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: A prospective observational study from the ZOE COVID. Study Lancet 2022,399(10335),1618-1624 - DOI - PubMed

[10] Menni C.; Valdes A.M.; Polidori L.; Antonelli M.; Penamakuri S.; Nogal A.; Louca P.; May A.; Figueiredo J.C.; Hu C.; Molteni E.; Canas L.; Österdahl M.F.; Modat M.; Sudre C.H.; Fox B.; Hammers A.; Wolf J.; Capdevila J.; Chan A.T.; David S.P.; Steves C.J.; Ourselin S.; Spector T.D.; Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: A prospective observational study from the ZOE COVID. Study Lancet 2022,399(10335),1618-1624 - DOI - PubMed

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

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

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