Soluble coxsackie- and adenovirus receptor (sCAR-Fc); a highly efficient compound against laboratory and clinical strains of coxsackie-B-virus

Pinkert, Sandra; Dieringer, Babette; Diedrich, Sabine; Zeichhardt, Heinz; Kurreck, Jens; Fechner, Henry

doi:10.1016/j.antiviral.2016.10.010

Cited by 13 publications

(17 citation statements)

References 38 publications

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“…Similar to that the extracellular part of the coxsackievirus and adenovirus receptor is used to inhibit Coxsackie-B-viruses, 9 recombinant human ACE2 (rhACE2) at clinical grade markedly reduces the early infection of SARS-CoV-2 and protects human blood vessel and kidney organoids. 10 Due to the natural location of ACE2 on the cell membrane, and because membrane with active ingredients are potential drug candidates, 11 we attempt to apply the membrane of human cells abundant of ACE2 to cope with SARS-CoV-2.…”

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confidence: 99%

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

Wang

Chen

et al. 2020

Preprint

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The ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg−1 of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19. Graphical Table of Contents

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confidence: 99%

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

Wang

Chen

et al. 2020

Preprint

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“…To assess whether resistant CVB3 mutants emerge during repeated exposure to sCAR-Fc, the laboratory strain CVB3 Nancy was serially passaged in HeLa cells after preincubation with 1 μg/ml sCAR-Fc. This amount represents an sCAR-Fc concentration that inhibited viral replication between 90% and 99% ( 22 ), allowing survival of enough virus progeny to enable passaging at a constant MOI. In two independent experiments, HeLa cells were subsequently infected after sCAR-Fc incubation, and replication was quantified after 24 h. The replication inhibition efficiency of sCAR-Fc was calculated relative to CVB3 Nancy replication after preincubation in the absence of sCAR-Fc.…”

Section: Resultsmentioning

confidence: 99%

“…The sCAR-Fc neutralizes all CVB serotypes (CVB1 to CVB6), and a prophylactic, as well as early therapeutic treatment, significantly inhibits CVB3-induced pancreatitis and myocarditis in mice ( 17 – 21 ). Recently, we have shown that not only various laboratory CVB strains but also 23 clinical strains are highly susceptible to sCAR-Fc-induced neutralization, isolated from patients with neurological or respiratory diseases ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Single-Point Mutations within the Coxsackie B Virus Receptor-Binding Site Promote Resistance against Soluble Virus Receptor Traps

Pinkert

Kopp

Brückner

et al. 2020

J Virol

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Coxsackie B viruses (CVB) cause a wide spectrum of diseases, ranging from mild respiratory syndromes and hand-foot-mouth disease to life-threatening conditions such as pancreatitis, myocarditis and encephalitis. Previously, we and others found that the soluble virus receptor trap sCAR-Fc strongly attenuates CVB3 infection in mice. In this study, we investigated whether treatment with sCAR-Fc result in development of resistance by CVB3. Two CVB3 strains (CVB3-H3 and CVB3 Nancy) were passaged in HeLa cells in presence of sCAR-Fc. The CVB3-H3 strain did not develop resistance, whereas two populations of CVB3 Nancy mutants emerged, one with complete (CVB3M) and one with partial (CVB3K) resistance. DNA sequence alignment of the resistant virus variant CVB3M with CVB3 Nancy revealed an amino acid exchange from Asn(N) to Ser(S) at position 139 of the CVB3 capsid protein VP2 (N2139S), an amino acid predicted to be involved in the virus's interaction with its cognate receptor CAR. Insertion of the N2139S mutation into CVB3-H3 by site-directed mutagenesis promoted resistance of the engineered CVB3-H3N2139S to sCAR-Fc. Interestingly, development of resistance by CVB3-H3N2139S and the exemplarily investigated CVB3M-clone 2 (CVB3M2) against soluble CAR did not compromise the use of cellular CAR for viral infection. Infection of HeLa cells showed that sCAR-Fc resistance, however, negatively affected both virus stability and the viral replication in comparison to the parental strains. These data demonstrate that during sCAR-Fc exposure, CVB3 can develop resistance against sCAR-Fc by single amino acid exchanges within the virus-receptor binding site, which, however, come at the expense of viral fitness. IMPORTANCE The emergence of resistant viruses is one of the most frequent obstacles preventing successful therapy of viral infections, thus representing a significant threat to human health. We investigated the emergence of resistant viruses during treatment with sCAR-Fc, a well-studied, highly effective antiviral molecule against CVB infections. Our data show the molecular aspects of resistant CVB3 mutants that arise during repetitive sCAR-Fc usage. However, drug resistance comes at the price of lower viral fitness. These results extend our knowledge of the development of resistance by coxsackieviruses and indicate potential limitations of antiviral therapy using soluble receptor molecules.

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“…In humans, the virus infects the gastrointestinal tract and typically induces local intestinal disease with mild flu‐like symptoms . Under certain circumstances, CVB3 can pass the local barrier of the intestine and spread via the bloodstream to other organs where it replicates to high titers and induces inflammatory disease, most commonly myocarditis , pancreatitis , and aseptic meningoencephalitis . CVB3 infection usually resolves by itself, but occasionally it progresses to severe disease which can have a fatal outcome.…”

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confidence: 99%

“…CVB3 infection usually resolves by itself, but occasionally it progresses to severe disease which can have a fatal outcome. There are many different strains of CVB3 with different phenotypic characteristics, leading to different courses of infection .…”

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confidence: 99%

MiR‐375‐mediated suppression of engineered coxsackievirus B3 in pancreatic cells

et al. 2019

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Coxsackievirus B3 (CVB3) has potential as a new oncolytic agent for the treatment of cancer but can induce severe pancreatitis. Here, we inserted target sequences of the microRNA miR‐375 (miR‐375TS) into the 5′ terminus of the polyprotein encoding sequence or into the 3′UTR of the CVB3 strain rCVB3.1 to prevent viral replication in the pancreas. In pancreatic EndoC‐βH1 cells expressing miR‐375 endogenously, replication of the 5′‐miR‐375TS virus and that of the 3′‐miR‐375TS virus was reduced by 4 × 103‐fold and 3.9 × 104‐fold, respectively, compared to the parental rCVB3.1. In colorectal carcinoma cells, replication and cytotoxicity of both viruses were slightly reduced compared to rCVB3.1, but less pronounced for the 3′‐miR‐375TS virus. Thus, CVB3 with miR‐375TS in the 3′UTR of the viral genome may be suitable to avoid pancreatic toxicity.

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Soluble coxsackie- and adenovirus receptor (sCAR-Fc); a highly efficient compound against laboratory and clinical strains of coxsackie-B-virus

Cited by 13 publications

References 38 publications

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

Single-Point Mutations within the Coxsackie B Virus Receptor-Binding Site Promote Resistance against Soluble Virus Receptor Traps

MiR‐375‐mediated suppression of engineered coxsackievirus B3 in pancreatic cells

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