tetano
Editor, Senior Moderator
J Virol. 2020 May 6. pii: JVI.00635-20. doi: 10.1128/JVI.00635-20. [Epub ahead of print]
Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity.
Zhu Y[SUP]1[/SUP], Yu D[SUP]1[/SUP], Yan H[SUP]1[/SUP], Chong H[SUP]1[/SUP], He Y[SUP]2[/SUP].
Author information
Abstract
The coronavirus disease COVID-19, caused by emerging SARS-CoV-2, has posed serious threats to global public health, economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we firstly verified that SARS-CoV-2 uses human ACE2 as a cell receptor and its spike (S) protein mediates high membrane fusion activity. Comparing to that of SARS-CoV, the heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR2) site. Then, we designed a HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly potent activities in inhibiting the SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus transduction. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the structure and activity relationship (SAR) of IPB02 was characterized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the presented results have provided important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step.IMPORTANCE The COVID-19 pandemic caused by SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. The S protein of coronaviruses mediates viral receptor-binding and membrane fusion thus being considered a critical target for antivirals. Herein, we report that the SARS-CoV-2 S protein evolves a high activity to mediate cell-cell fusion, significantly differing from the S protein of the previously emerged SARS-CoV. In comparison, the HR1 sequence in the fusion protein of SARS-CoV-2 adopts a much higher helical stability and can interact with the HR2 site to form a six-helical bundle structure more efficiently, underlying the mechanism of the enhanced fusion capacity. Also importantly, the design of membrane fusion inhibitors with high potencies against both SARS-CoV-2 and SARS-CoV has provided potential arsenals to combat the pandemic and tools to exploit the fusion mechanism.
Copyright ? 2020 American Society for Microbiology.
PMID:32376627DOI:10.1128/JVI.00635-20
Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity.
Zhu Y[SUP]1[/SUP], Yu D[SUP]1[/SUP], Yan H[SUP]1[/SUP], Chong H[SUP]1[/SUP], He Y[SUP]2[/SUP].
Author information
Abstract
The coronavirus disease COVID-19, caused by emerging SARS-CoV-2, has posed serious threats to global public health, economic and social stabilities, calling for the prompt development of therapeutics and prophylactics. In this study, we firstly verified that SARS-CoV-2 uses human ACE2 as a cell receptor and its spike (S) protein mediates high membrane fusion activity. Comparing to that of SARS-CoV, the heptad repeat 1 (HR1) sequence in the S2 fusion protein of SARS-CoV-2 possesses markedly increased α-helicity and thermostability, as well as a higher binding affinity with its corresponding heptad repeat 2 (HR2) site. Then, we designed a HR2 sequence-based lipopeptide fusion inhibitor, termed IPB02, which showed highly potent activities in inhibiting the SARS-CoV-2 S protein-mediated cell-cell fusion and pseudovirus transduction. IPB02 also inhibited the SARS-CoV pseudovirus efficiently. Moreover, the structure and activity relationship (SAR) of IPB02 was characterized with a panel of truncated lipopeptides, revealing the amino acid motifs critical for its binding and antiviral capacities. Therefore, the presented results have provided important information for understanding the entry pathway of SARS-CoV-2 and the design of antivirals that target the membrane fusion step.IMPORTANCE The COVID-19 pandemic caused by SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. The S protein of coronaviruses mediates viral receptor-binding and membrane fusion thus being considered a critical target for antivirals. Herein, we report that the SARS-CoV-2 S protein evolves a high activity to mediate cell-cell fusion, significantly differing from the S protein of the previously emerged SARS-CoV. In comparison, the HR1 sequence in the fusion protein of SARS-CoV-2 adopts a much higher helical stability and can interact with the HR2 site to form a six-helical bundle structure more efficiently, underlying the mechanism of the enhanced fusion capacity. Also importantly, the design of membrane fusion inhibitors with high potencies against both SARS-CoV-2 and SARS-CoV has provided potential arsenals to combat the pandemic and tools to exploit the fusion mechanism.
Copyright ? 2020 American Society for Microbiology.
PMID:32376627DOI:10.1128/JVI.00635-20