Functional Analysis of Human and Feline Coronavirus Cross-Reactive Antibodies Directed Against the SARS-CoV-2 Fusion Peptide

To face the continuous emergence of SARS-CoV-2 variants, broadly protective therapeutic antibodies are highly needed. We here focused on the fusion peptide (FP) region of the viral spike antigen since it is highly conserved among alpha- and betacoronaviruses. First, we found that coronavirus cross-reactive antibodies are commonly formed during infection, being omnipresent in sera from COVID-19 patients, in ~50% of pre-pandemic human sera (rich in antibodies against endemic human coronaviruses), and even in feline coronavirus-infected cats. Pepscan analyses demonstrated that a confined N-terminal region of the FP is strongly immunogenic across diverse coronaviruses. Peptide-purified human antibodies targeting this conserved FP epitope exhibited broad binding of alpha- and betacoronaviruses, besides weak and transient SARS-CoV-2 neutralizing activity. Being frequently elicited by coronavirus infection, these FP-binding antibodies might potentially exhibit Fc-mediated effector functions and influence the kinetics or severity of coronavirus infection and disease.

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The Population Diversity of Candidate Genes for Resistance/Susceptibility to Coronavirus Infection in Domestic Cats: An Inter-Breed Comparison

Pathogens ◽

10.3390/pathogens10060778 ◽

2021 ◽

Vol 10 (6) ◽

pp. 778

Author(s):

Jana Bubenikova ◽

Leona Vychodilova ◽

Karla Stejskalova ◽

Jan Futas ◽

Jan Oppelt ◽

...

Keyword(s):

Candidate Genes ◽

Single Gene ◽

Differential Susceptibility ◽

Snp Markers ◽

Population Diversity ◽

Population Substructure ◽

Domestic Cats ◽

Coronavirus Infection ◽

Breed Comparison ◽

Feline Coronavirus

Feline coronavirus (FCoV) is a complex pathogen causing feline infectious peritonitis (FIP). Host genetics represents a factor contributing to the pathogenesis of the disease. Differential susceptibility of various breeds to FIP was reported with controversial results. The objective of this study was to compare the genetic diversity of different breeds on a panel of candidate genes potentially affecting FCoV infection. One hundred thirteen cats of six breeds were genotyped on a panel of sixteen candidate genes. SNP allelic/haplotype frequencies were calculated; pairwise FST and molecular variance analyses were performed. Principal coordinate (PCoA) and STRUCTURE analyses were used to infer population structure. Interbreed differences in allele frequencies were observed. PCoA analysis performed for all genes of the panel indicated no population substructure. In contrast to the full marker set, PCoA of SNP markers associated with FCoV shedding (NCR1 and SLX4IP) showed three clusters containing only alleles associated with susceptibility to FCoV shedding, homozygotes and heterozygotes for the susceptibility alleles, and all three genotypes, respectively. Each cluster contained cats of multiple breeds. Three clusters of haplotypes were identified by PCoA, two clusters by STRUCTURE. Haplotypes of a single gene (SNX5) differed significantly between the PCoA clusters.

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Serological Diagnosis of Feline Coronavirus Infection by Immunochromatographic Test

Coronaviruses - Methods in Molecular Biology ◽

10.1007/978-1-4939-2438-7_3 ◽

2015 ◽

pp. 33-39 ◽

Cited By ~ 2

Author(s):

Tomomi Takano ◽

Tsutomu Hohdatsu

Keyword(s):

Serological Diagnosis ◽

Immunochromatographic Test ◽

Coronavirus Infection ◽

Feline Coronavirus

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Advances in the assessment and control of the effector functions of therapeutic antibodies

Nature Reviews Drug Discovery ◽

10.1038/nrd3365 ◽

2011 ◽

Vol 10 (2) ◽

pp. 101-111 ◽

Cited By ~ 207

Author(s):

Xu-Rong Jiang ◽

An Song ◽

Svetlana Bergelson ◽

Thomas Arroll ◽

Bhavin Parekh ◽

...

Keyword(s):

Therapeutic Antibodies ◽

Effector Functions ◽

And Control

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Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

Science ◽

10.1126/science.abe3354 ◽

2020 ◽

Vol 370 (6519) ◽

pp. 950-957 ◽

Cited By ~ 21

Author(s):

M. Alejandra Tortorici ◽

Martina Beltramello ◽

Florian A. Lempp ◽

Dora Pinto ◽

Ha V. Dang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Viral Escape ◽

Angiotensin Converting Enzyme 2 ◽

Effector Functions ◽

Human Antibodies ◽

Binding Domains ◽

Isolation And Characterization ◽

Cryo Electron Microscopy ◽

Escape Mutants

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo–electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.

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Class-Specific Effector Functions of Therapeutic Antibodies

Methods in Molecular Biology - Antibody Methods and Protocols ◽

10.1007/978-1-61779-931-0_19 ◽

2012 ◽

pp. 295-317 ◽

Cited By ~ 1

Author(s):

Virginie Pascal ◽

Brice Laffleur ◽

Michel Cogné

Keyword(s):

Therapeutic Antibodies ◽

Effector Functions ◽

Specific Effector

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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Nature Communications ◽

10.1038/s41467-020-18096-2 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 19

Author(s):

Wayne Vuong ◽

Muhammad Bashir Khan ◽

Conrad Fischer ◽

Elena Arutyunova ◽

Tess Lamer ◽

...

Keyword(s):

Drug Target ◽

Covalent Modification ◽

Human Coronavirus ◽

Feline Infectious Peritonitis ◽

Drug Candidates ◽

Main Protease ◽

Coronavirus Infection ◽

Reversible Formation ◽

Nanomolar Range ◽

Feline Coronavirus

Abstract The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.

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Antiviral Effects of Hydroxychloroquine and Type I Interferon on In Vitro Fatal Feline Coronavirus Infection

Viruses ◽

10.3390/v12050576 ◽

2020 ◽

Vol 12 (5) ◽

pp. 576 ◽

Cited By ~ 4

Author(s):

Tomomi Takano ◽

Kumi Satoh ◽

Tomoyoshi Doki ◽

Taishi Tanabe ◽

Tsutomu Hohdatsu

Keyword(s):

Viral Infections ◽

Viral Disease ◽

High Morbidity ◽

Type I ◽

Feline Infectious Peritonitis ◽

Antiviral Effects ◽

Immune Mediated ◽

Coronavirus Infection ◽

Feline Coronavirus

Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and mortality by the FIP virus (FIPV, virulent feline coronavirus). Several antiviral drugs for FIP have been identified, but many of these are expensive and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. We investigated whether HCQ in association with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 μM of HCQ significantly inhibited the replication of types I and II FIPV. Interestingly, the combination of 100 μM of HCQ and 104 U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω are applicable for treatment of FIP. Further clinical studies are needed to verify the combination of HCQ and rIFN-ω will be effective and safe treatment for cats with FIP.

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