Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein

Xia, Shuai; Zhu, Yun; Liu, Meiqin; Lan, Qiaoshuai; Xu, Wei; Wu, Yanling; Ying, Tianlei; Liu, Shuwen; Z, Shi; Jiang, Shibo; Lu, Lu

doi:10.1038/s41423-020-0374-2

Cited by 659 publications

(774 citation statements)

References 8 publications

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“…Spike glycoprotein consists of S1 and S2 subunits. The S1 subunit contains a signal peptide, an N-terminal domain (NTD) and RBD, while the S2 subunit includes the conserved fusion peptide (FP), heptad repeat 1 and 2 (HR1 and HR2), transmembrane domain (TM), and cytoplasmic domain (CP) [102,105]. Furthermore, the S2 subunit of SARS-CoV-2 is highly conserved and shares 99% similarity with those of Bat-SL-CoVZC45, Bat-SL-CoVZC21 and human SARS-CoV [102].…”

Section: Case Diagnostic Criteria Suspected Casementioning

confidence: 99%

The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China

Yang

Peng

Wang

et al. 2020

Journal of Autoimmunity

911

858

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COVID-19 pandemic, an unprecedented devastation, humanity needs an urgent cure to save the mankind from this deadly disease. Over six million people have been infected worldwide, with 6.3% reported deaths till date. SARS-CoV-2 virus, responsible for Novel Coronavirus (COVID-19) disease has been isolated recently and the vaccine's development is at nascent stage. At present, there are a few anecdotal evidences that anti-viral/anti-in ammatory/anti-malarial drugs can mitigate the disease. In the present study, we envision the potency of traditional Indian medicinal compounds that can be used as an effective drug. The viral SARS Coronavirus E protein plays a key role in virus life cycle and can be a potential drug target for the development of anti-SARS-CoV-2 drugs. Using the crystal structure of the CoVE protein, we performed virtual PyRX screening of Indian medicinal compounds which are reported to have e cacy in the treatment of some viral infections. Molecular docking studies were evaluated based on scores analysed by CavityPlus. The herbal compounds used were found to be more e cient in inhibiting the virus as compared to commercially available drugs. The results showed that β-boswellic acid and Glycyrrhizic acid possessed the best binding as a ligand with target molecule having binding a nity of-9.1 kcal/mol amongst eleven compounds screened. The study demonstrated that these are found to be strong SARS-CoV-2E protein inhibitors as they revealed compatible, near perfect dock in the overlapping region of functional viral protein pockets. These potential hit compounds can pave a way for designing of anti-viral therapeutics.

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Section: Case Diagnostic Criteria Suspected Casementioning

confidence: 99%

The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China

Yang

Peng

Wang

et al. 2020

Journal of Autoimmunity

911

858

View full text Add to dashboard Cite

show abstract

“…14 Indeed, our recent studies have shown that EK1 peptide is effective against SARS-CoV-2 S proteinmediated membrane fusion and PsV infection in a dosedependent manner. 15 In this study, we have shown that SARS-CoV-2 exhibits much higher capacity of membrane fusion than SARS-CoV, suggesting that the fusion machinery of SARS-CoV-2 is an important target for development of coronavirus fusion inhibitors. We have solved the X-ray crystal structure of SARS-CoV-2's 6-HB core and identified several mutated amino acid residues in HR1 domain responsible for its enhanced interactions with HR2 domain.…”

Section: Introductionmentioning

confidence: 81%

“…As expected, we recently have shown that EK1 is also effective in inhibiting infection of the novel β-CoV, SARS-CoV-2. 15 We then optimized EK1 peptide in hopes of improving its fusion inhibitory activity. Indeed, we found that one of the modified EK1 peptides, EK1C4, was 226-fold and 149-fold more potent against SARS-CoV-2 S protein-mediated membrane fusion and PsV infection, respectively, than EK1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Xia

Liu

Wang³

et al. 2020

Cell Res

Self Cite

1,214

1,420

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The recent outbreak of coronavirus disease caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241-and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.

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“…S glycoprotein includes two subunits, S1 and S2 [30]. S1 determines the virus-host range and cellular tropism with the key function domain − RBD, while S2 mediates virus-cell membrane fusion by two tandem domains, heptad repeats 1 (HR1) [31] and HR2 [32]. After membrane fusion, the viral genome RNA is released into the cytoplasm, and the uncoated RNA translates two polyproteins, pp1a and pp1ab [33], which encode non-structural proteins, and form replication-transcription complex (RTC) in double-membrane vesicle [34].…”

Section: Coronavirus Replication and Pathogenesismentioning

confidence: 99%

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

et al. 2020

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An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

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Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein

Cited by 659 publications

References 8 publications

The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China

The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

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