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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315882

ABSTRACT

Background: The outbreak and pandemic of coronavirus SARS CoV 2 caused significant threaten to global public health and economic consequences. It is extremely urgent that global people must take actions to develop safe and effective preventions and therapeutics. Nanobodies, which are derived from single‑chain camelid antibodies, had shown antiviral properties in various challenge viruses. In this study, multivalent nanobodies with high affinity blocking SARS CoV 2 spike interaction with ACE2 protein were developed. Results: Totally, four specific nanobodies against spike protein and its RBD domain were screened from a naïve VHH library. Among them, Nb91 hFc and Nb3 hFc demonstrated antiviral activity by neutralizing spike pseudotyped viruses in vitro. Subsequently, multivalent nanobodies were constructed to improve the neutralizing capacity. As a result, heterodimer nanobody Nb91 Nb3 hFc exhibited the strongest RBD binding affinity and neutralizing ability against SARS CoV 2 pseudoviruses with an IC50 value at approximately 1.54 nM. Conclusions: The present study indicated that naïve VHH library could be used as a potential resource for rapid acquisition and exploitation of antiviral nanobodies. Heterodimer nanobody Nb91 Nb3 hFc may serve as a potential therapeutic agent for the treatment of COVID 19.

2.
MedComm ; 2021.
Article in English | EuropePMC | ID: covidwho-1567268

ABSTRACT

SARS‐CoV‐2 is an enveloped positive‐sense RNA virus that depends on host factors for all stages of its life. Membrane receptor ACE2 is a well‐established factor for SARS‐CoV‐2 docking. In addition to ACE2, whole‐genome genetic screens have identified additional proteins, such as endosomal trafficking regulators SNX27 and retromer, as key host factors required for SARS‐CoV‐2 infection. However, it is poorly understood how SARS‐CoV‐2 utilize host endocytic transport pathways to produce productive infection. Here, we report that SNX27 interacts with the SARS‐CoV‐2 spike (S) protein to facilitate S protein surface expression. Interestingly, S protein binds to the PDZ domain of SNX27, although it does not contain a PDZ‐binding motif (PDZbm). Either abrogation of the SNX27 PDZ domain or S protein “MTSC” motif, which is critical for SNX27 binding, decreases surface expression of S protein and viral production. Collectively, our study highlights a novel approach utilized by SARS‐CoV‐2 to facilitate virion trafficking to establish virus infection. Proposed model showing SNX27 promotes intracellular trafficking of S protein and viral production. (a) SNX27, via its PDZ domain, interacts with S protein and promotes endosome‐to‐plasma membrane trafficking of S protein. SNX27 could also promote the production of SARS‐CoV‐2 virions in host cells, although the mechanism remains poorly defined. (b) Depletion of SNX27 impairs endosome‐to‐plasma membrane trafficking of S protein, leading to its lysosomal degradation.

4.
J Nanobiotechnology ; 19(1): 33, 2021 Jan 29.
Article in English | MEDLINE | ID: covidwho-1054825

ABSTRACT

BACKGROUND: The outbreak and pandemic of coronavirus SARS-CoV-2 caused significant threaten to global public health and economic consequences. It is extremely urgent that global people must take actions to develop safe and effective preventions and therapeutics. Nanobodies, which are derived from single­chain camelid antibodies, had shown antiviral properties in various challenge viruses. In this study, multivalent nanobodies with high affinity blocking SARS-CoV-2 spike interaction with ACE2 protein were developed. RESULTS: Totally, four specific nanobodies against spike protein and its RBD domain were screened from a naïve VHH library. Among them, Nb91-hFc and Nb3-hFc demonstrated antiviral activity by neutralizing spike pseudotyped viruses in vitro. Subsequently, multivalent nanobodies were constructed to improve the neutralizing capacity. As a result, heterodimer nanobody Nb91-Nb3-hFc exhibited the strongest RBD-binding affinity and neutralizing ability against SARS-CoV-2 pseudoviruses with an IC50 value at approximately 1.54 nM. CONCLUSIONS: The present study indicated that naïve VHH library could be used as a potential resource for rapid acquisition and exploitation of antiviral nanobodies. Heterodimer nanobody Nb91-Nb3-hFc may serve as a potential therapeutic agent for the treatment of COVID-19.


Subject(s)
Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites , HEK293 Cells , Humans , Neutralization Tests , Protein Binding , Protein Domains , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
6.
Nature ; 586(7830): 572-577, 2020 10.
Article in English | MEDLINE | ID: covidwho-691301

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.


Subject(s)
Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , COVID-19 , COVID-19 Vaccines , Humans , Macaca mulatta/immunology , Macaca mulatta/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Animal , Models, Molecular , Protein Domains , SARS-CoV-2 , Serum/immunology , Spleen/cytology , Spleen/immunology , T-Lymphocytes/immunology , Vaccination
7.
Front Neurol ; 11: 659, 2020.
Article in English | MEDLINE | ID: covidwho-634494

ABSTRACT

SARS-CoV-2 is a novel coronavirus leading to serious respiratory disease and is spreading around the world at a raging speed. Recently there is emerging speculations that the central nervous system (CNS) may be involved during SARS-CoV-2 infection, contributing to the respiratory failure. However, the existence of viral replication in CNS has not been confirmed due to the lack of evidence from autopsy specimens. Considering the tropism of SARS-CoV-2, ACE2, is prevailing in CNS, and the neuro-invasive property of human coronavirus was widely reported, there is a need to identified the possible complications during COVID-19 for CNS. In this review, we conduct a detailed summary for the potential of SARS-CoV-2 to infect central nervous system from latest biological fundamental of SARS-CoV-2 to the clinical experience of other human coronaviruses. To confirm the neuro-invasive property of SARS-CoV-2 and the subsequent influence on patients will require further exploration by both virologist and neurologist.

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