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1.
Front Microbiol ; 13: 884034, 2022.
Article in English | MEDLINE | ID: covidwho-1847188

ABSTRACT

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), public health worldwide has been greatly threatened. The development of an effective treatment for this infection is crucial and urgent but is hampered by the incomplete understanding of the viral infection mechanisms and the lack of specific antiviral agents. We previously reported that teicoplanin, a glycopeptide antibiotic that has been commonly used in the clinic to treat bacterial infection, significantly restrained the cell entry of Ebola virus, SARS-CoV, and MERS-CoV by specifically inhibiting the activity of cathepsin L (CTSL). Here, we found that the cleavage sites of CTSL on the spike proteins of SARS-CoV-2 were highly conserved among all the variants. The treatment with teicoplanin suppressed the proteolytic activity of CTSL on spike and prevented the cellular infection of different pseudotyped SARS-CoV-2 viruses. Teicoplanin potently prevented the entry of SARS-CoV-2 into the cellular cytoplasm with an IC50 of 2.038 µM for the Wuhan-Hu-1 reference strain and an IC50 of 2.116 µM for the SARS-CoV-2 (D614G) variant. The pre-treatment of teicoplanin also prevented SARS-CoV-2 infection in hACE2 mice. In summary, our data reveal that CTSL is required for both SARS-CoV-2 and SARS-CoV infection and demonstrate the therapeutic potential of teicoplanin for universal anti-CoVs intervention.

2.
Adv Sci (Weinh) ; 9(11): e2105378, 2022 04.
Article in English | MEDLINE | ID: covidwho-1680239

ABSTRACT

The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.


Subject(s)
COVID-19 , Nanoparticles , Animals , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Macaca mulatta/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Conjugate
3.
Cell Rep ; 38(3): 110256, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1588136

ABSTRACT

Inoculation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing worldwide. However, the emergence of SARS-CoV-2 variants could cause immune evasion. We developed a bivalent nanoparticle vaccine that displays the receptor binding domains (RBDs) of the D614G and B.1.351 strains. With a prime-boost or a single-dose strategy, this vaccine elicits a robust neutralizing antibody and full protection against infection with the authentic D614G or B.1.351 strain in human angiotensin-converting enzyme 2 transgene mice. Interestingly, 8 months after inoculation with the D614G-specific vaccine, a new boost with this bivalent vaccine potently elicits cross-neutralizing antibodies for SARS-CoV-2 variants in rhesus macaques. We suggest that the D614G/B.1.351 bivalent vaccine could be used as an initial single dose or a sequential enforcement dose to prevent infection with SARS-CoV-2 and its variants.


Subject(s)
COVID-19/prevention & control , Cross Protection , SARS-CoV-2/immunology , Vaccines, Combined/therapeutic use , Animals , CHO Cells , COVID-19 Vaccines/chemical synthesis , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Chlorocebus aethiops , Cricetulus , Cross Protection/immunology , Female , HEK293 Cells , Humans , Macaca mulatta , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Nanoparticles , Vaccination/methods , Vaccines, Combined/chemical synthesis , Vaccines, Combined/immunology , Vero Cells
7.
Immunity ; 53(6): 1315-1330.e9, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-967948

ABSTRACT

Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.


Subject(s)
Bacterial Proteins/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Ferritins/immunology , Helicobacter pylori/metabolism , Recombinant Fusion Proteins/immunology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Bacterial Proteins/chemistry , COVID-19 Vaccines/chemistry , Ferritins/chemistry , Humans , Macaca mulatta , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Pandemics , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Vaccination
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