Pan-coronavirus fusion inhibitors possess potent inhibitory activity against HIV-1, HIV-2, and simian immunodeficiency virus

Yu, Danwei; Zhu, Yuanmei; Huang, Yan; Wu, Tong Tong; Chong, Huihui; He, Yuxian

doi:10.1080/22221751.2021.1917309

Cited by 16 publications

(12 citation statements)

References 39 publications

(50 reference statements)

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“…We found that the S protein of SARS-CoV-2 has a much higher fusogenic activity than the S protein of SARS-CoV and its HR2-derived fusion inhibitors exhibits potent and broad-spectrum inhibitory activity against divergent human CoVs [ 31 , 32 ]. Interestingly, several pan-CoV fusion inhibitors, including EK1V1, EK1C4, and IPB02, were serendipitously found to have cross-inhibitory activities against divergent HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates [ 51 ]. In this study, we continued our efforts to develop SARS-CoV-2 fusion inhibitors with improved pharmaceutical profiles.…”

Section: Discussionmentioning

confidence: 99%

Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants

Zhu

Jiao

et al. 2021

Emerging Microbes & Infections

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The ongoing pandemic of COVID-19, caused by SARS-CoV-2, has severely impacted the global public health and socio-economic stability, calling for effective vaccines and therapeutics. In this study, we continued our efforts to develop more efficient SARS-CoV-2 fusion inhibitors and achieved significant findings. First, we found that the membrane-proximal external region (MPER) sequence of SARS-CoV-2 spike fusion protein plays a critical role in viral infectivity and can serve as an ideal template for design of fusion-inhibitory peptides. Second, a panel of novel lipopeptides was generated with greatly improved activity in inhibiting SARS-CoV-2 fusion and infection. Third, we showed that the new inhibitors maintained the potent inhibitory activity against emerging SARS-CoV-2 variants, including those with the major mutations of the B.1.1.7 and B.1.351 strains circulating in the United Kingdom and South Africa, respectively. Fourth, the new inhibitors also cross-inhibited other human CoVs, including SARS-CoV, MERS-CoV, HCoV-229E, and HCoV-NL63. Fifth, the structural properties of the new inhibitors were characterized by circular dichroism (CD) spectroscopy and crystallographic approach, which revealed the mechanisms underlying the high binding and inhibition. Combined, our studies provide important information for understanding the mechanism of SARS-CoV-2 fusion and a framework for the development of peptide therapeutics for the treatment of SARS-CoV-2 and other CoVs.

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Section: Discussionmentioning

confidence: 99%

Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants

Zhu

Jiao

et al. 2021

Emerging Microbes & Infections

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“…Yuxian He and co-workers have synthesized a lipo-peptide EK1V1 by modifying EK1 with cholesterol, which exhibited significantly improved antiviral activity. EK1V1 displayed potent cross inhibitory activities against divergent HIV-1, HIV-2, and simian immunodeficiency virus (SIV) (Yu et al 2021 ). Another EK1 derivative, the lipo-peptide EK1C4 increases the inhibitory activity against the SARS-CoV-2 and HIV-1 infection (Xia et al 2020 ).…”

Section: Lipid Anchor and Virus Entry Inhibitormentioning

confidence: 99%

Lipid and Lipidation in Membrane Fusion

et al. 2022

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Membrane fusion plays a lead role in the transport of vesicles, neurotransmission, mitochondrial dynamics, and viral infection. There are fusion proteins that catalyze and regulate the fusion. Interestingly, various types of fusion proteins are present in nature and they possess diverse mechanisms of action. We have highlighted the importance of the functional domains of intracellular heterotypic fusion, homotypic endoplasmic reticulum (ER), homotypic mitochondrial, and type-I viral fusion. During intracellular heterotypic fusion, the SNAREs and four-helix bundle formation are prevalent. Type-I viral fusion is controlled by the membrane destabilizing properties of fusion peptide and six-helix bundle formation. The ER/mitochondrial homotypic fusion is controlled by GTPase activity and the membrane destabilization properties of the amphipathic helix(s). Although the mechanism of action of these fusion proteins is diverse, they have some similarities. In all cases, the lipid composition of the membrane greatly affects membrane fusion. Next, examples of lipidation of the fusion proteins were discussed. We suggest that the fatty acyl hydrophobic tail not only acts as an anchor but may also modulate the energetics of membrane fusion intermediates. Lipidation is also important to design more effective peptide-based fusion inhibitors. Together, we have shown that membrane lipid composition and lipidation are important to modulate membrane fusion. Graphical Abstract

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“…EK1C4 can effectively protect mice from infection by intranasal administration before or after the HCoV-OC43 attack, which indicates that EK1C4 can be used to prevent and treat infections caused by SARS-CoV-2 and other emerging coronaviruses [ 15 ]. Moreover, another lipopeptide, EK1V1, generated by adding cholesterol to the EK1, exhibits significantly improved antiviral activity against human coronaviruses, HIV-1, HIV-2, and SIV (simian immunodeficiency virus) [ 70 ], which indicated that lipopeptide EK1 and its derivatives are promising virus fusion inhibitors with broad-spectrum antivirals.…”

Section: Targets For Pan-coronavirus Inhibitorsmentioning

confidence: 99%

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

Zhang

Chen

et al. 2021

Microorganisms

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which caused Coronaviruses Disease 2019 (COVID-19) and a worldwide pandemic, is the seventh human coronavirus that has been cross-transmitted from animals to humans. It can be predicted that with continuous contact between humans and animals, more viruses will spread from animals to humans. Therefore, it is imperative to develop universal coronavirus or pan-coronavirus vaccines or drugs against the next coronavirus pandemic. However, a suitable target is critical for developing pan-coronavirus antivirals against emerging or re-emerging coronaviruses. In this review, we discuss the latest progress of possible targets of pan-coronavirus antiviral strategies for emerging or re-emerging coronaviruses, including targets for pan-coronavirus inhibitors and vaccines, which will provide prospects for the current and future research and treatment of the disease.

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Pan-coronavirus fusion inhibitors possess potent inhibitory activity against HIV-1, HIV-2, and simian immunodeficiency virus

Cited by 16 publications

References 39 publications

Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants

Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants

Lipid and Lipidation in Membrane Fusion

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

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