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

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          Abstract

          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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          Coronavirus biology and replication: implications for SARS-CoV-2

          Philip V’kovski, Annika Kratzel, Silvio Steiner … (2020)
          The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.
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            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

            Shuai Xia, Meiqin Liu, Chao Fu Wang … (2020)
            The recent outbreak of coronavirus disease (COVID-19) 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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              Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

              Wilfredo Garcia-Beltran, Evan Lam, Kerri St. Denis … (2021)
              Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2. Five of the 10 pseudoviruses, harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.
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                Author and article information

                Contributors
                Keivan Zandi: Role: Academic Editor
                James J. Kohler: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Microorganisms
                Journal ID (iso-abbrev): Microorganisms
                Journal ID (publisher-id): microorganisms
                Title: Microorganisms
                Publisher: MDPI
                ISSN (Electronic): 2076-2607
                Publication date (Electronic): 10 July 2021
                Publication date Collection: July 2021
                Volume: 9
                Issue: 7
                Electronic Location Identifier: 1479
                Affiliations
                Key Laboratory for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, 5333 Xi’An Road, Changchun 130062, China; Lix9916@ 123456mails.jlu.edu.cn (X.L.); zhangliy@ 123456jlu.edu.cn (L.Z.); chensi_1024@ 123456163.com (S.C.); ouyh@ 123456jlu.edu.cn (H.O.)
                Author notes
                [* ]Correspondence: renlz@ 123456jlu.edu.cn
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-1092-6435
                Article
                Publisher ID: microorganisms-09-01479
                DOI: 10.3390/microorganisms9071479
                PMC ID: 8306356
                PubMed ID: 34361915
                SO-VID: c2b89aa9-9318-4a84-89dd-0fbe3e4d41c6
                Copyright © © 2021 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 21 June 2021
                Date accepted : 09 July 2021
                Categories
                Subject: Review

                Keywords: pan-coronavirus,target,inhibitor,vaccine,epitope
                Data availability:
                Keywords: pan-coronavirus, target, inhibitor, vaccine, epitope

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