Peptide-based pan-CoV fusion inhibitors maintain high potency against SARS-CoV-2 Omicron variant

Xia, Shuai; Chan, Jasper Fuk‐Woo; Wang, Lijue; Jiao, Fanke; Chik, Kenn Ka-Heng; Chu, Hin; Lan, Qiaoshuai; Xu, Wei; Wang, Qian; Chao, Wang; Yuen, Kwok‐Yung; Lu, Lu; Jiang, Shibo

doi:10.1038/s41422-022-00617-x

Cited by 37 publications

(41 citation statements)

References 11 publications

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“…In contrast, shared mutations of N440K and D614G, as well as BA.1-specific changes of Δ69-70, Δ211, insertion of 214EPE, and mutation of L981F increased infection efficiencies. Our results agree with recent findings suggesting that the Q954H and N969K changes in heptad repeat 1 (HR1) reduce rather than enhance fusion efficiency (Suzuki et al, 2022; Xia et al, 2022; Zhao et al, 2021). In addition, our analysis revealed that N856K in BA.1 S and T19I as well as Δ24-26 in the BA.2 NTD strongly impaired S-mediated infection.…”

Section: Resultssupporting

confidence: 93%

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Pastorio

Zech

Noettger

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission, immune evasion and pathogenicity is thought to be driven by numerous mutations in the Omicron Spike protein. Here, we examined the impact of amino acid changes that are characteristic for the BA.1 and/or BA.2 Omicron lineages on Spike function, processing and susceptibility to neutralization. Individual mutations of S371F/L, S375F and T376A in the ACE2 receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes of G339D, D614G, N764K and L981F moderately enhanced it. Most mutations in the N-terminal region and the receptor binding domain reduced sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine or therapeutic antibodies. Our results represent a systematic functional analysis of Omicron Spike adaptations that allowed this SARS-CoV-2 variant to overtake the current pandemic.

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Section: Resultssupporting

confidence: 93%

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Pastorio

Zech

Noettger

et al. 2022

Preprint

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“…We previously identified a series of peptide-based fusion/entry inhibitors targeting the HR1 domain of HIV-1 (e.g., SJ-2176) [ 30 ], SARS-CoV (SC-1) [ 31 ], MERS-CoV (MERS-HR2P) [ 32 ], HCoV-OC43 (OC43-HR2P) [ 5 ] and SARS-CoV-2 (2019-nCoV-HR2P) [ 6 ], as well as to pan-CoV, including EK1 [ 5 ], EK1C4 [ 7 , 33 ] and EKL1C [ 8 ]. Notwithstanding these advances, HR2 should be a better target for the development of broad-spectrum HCoV fusion/entry inhibitors since the amino acid sequence of the HR2 domain is more conserved than that of HR1.…”

Section: Discussionmentioning

confidence: 99%

A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern

Xing

et al. 2022

Viruses

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The prolonged duration of the severe acute respiratory syndrome coronavirus−2 (SARS−CoV−2) pandemic has resulted in the continuous emergence of variants of concern (VOC, e.g., Omicron) and variants of interest (VOI, e.g., Lambda). These variants have challenged the protective efficacy of current COVID−19 vaccines, thus calling for the development of novel therapeutics against SARS−CoV−2 and its VOCs. Here, we constructed a novel fusion inhibitor−based recombinant protein, denoted as 5−Helix, consisting of three heptad repeat 1 (HR1) and two heptad repeat 2 (HR2) fragments. The 5−Helix interacted with the HR2 domain of the viral S2 subunit, the most conserved region in spike (S) protein, to block homologous six−helix bundle (6−HB) formation between viral HR1 and HR2 domains and, hence, viral S−mediated cell–cell fusion. The 5−Helix potently inhibited infection by pseudotyped SARS−CoV−2 and its VOCs, including Delta and Omicron variants. The 5−Helix also inhibited infection by authentic SARS−CoV−2 wild−type (nCoV−SH01) strain and its Delta variant. Collectively, our findings suggest that 5−Helix can be further developed as either a therapeutic or prophylactic to treat and prevent infection by SARS−CoV−2 and its variants.

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“…We found that EK1 peptide targeting the HR1 domain of divergent HCoVs could broadly and effectively inhibit infection of all HCoVs and bat SARSr-CoVs tested [ 27 ]. Our cholesterol-conjugated EK1 lipopeptide, EK1C4, showed significant improvement in its inhibitory activity against SARS-CoV-2 and its VOCs, including Omicron [ 17 , 19 ]. However, while no cholesterol-based lipopeptides are currently in clinical use, some C16-based lipopeptide drugs are in clinical trials, showing the practicality of developing a C16-conjugated lipopeptide drug, as we have herein reported.…”

Section: Discussionmentioning

confidence: 99%

“…We and others demonstrated that peptides derived from the HR2 domain of SARS-CoV-2, such as 2019-nCoV-HR2P, IPB01, and SARS-CoV-2-HRC, could potently inhibit SARS-CoV-2 infection by interacting with the HR1 domain of SARS-CoV-2 S protein to block the formation of 6-HB fusion core between viral HR1 and HR2 domains [ 14 , 15 , 16 ]. In particular, our previously developed pan-CoV fusion inhibitor EK1 is effective against infection by SARS-CoV-2 D614G and its VOCs [ 17 , 18 , 19 ]. Later, we found that cholesterol- and 25-hydroxycholesterol-conjugated EK1 peptides, such as EK1C4 [ 17 ], EKL1C [ 20 ], and EK1P4HC [ 21 ], exhibited much improved antiviral activity against SARS-CoV-2, its VOCs, and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, and HCoV-OC43, as well as bat SARSr-CoV WIV1, SARSr-CoV Rs3367, and SARSr-CoV SHC014.…”

Section: Introductionmentioning

confidence: 99%

A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern

Lan

Chan

et al. 2022

Viruses

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Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.

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Peptide-based pan-CoV fusion inhibitors maintain high potency against SARS-CoV-2 Omicron variant

Cited by 37 publications

References 11 publications

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern

A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern

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