Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates

Mathieu, Cyrille; Porotto, Matteo; Figueira, Tiago N.; Horvat, Branka; Moscona, Anne

doi:10.1093/infdis/jiy152

Cited by 46 publications

(48 citation statements)

References 46 publications

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“…Recently, numerous reports have shown that the lipidation strategy can effectively improve the antiviral activity of fusion inhibitory peptides, such as the ant-HIV-1 peptide LP-19, 18 and the anti-Nipah virus lipopeptides. 19 In order to improve the inhibitory activity of EK1, cholesterol (Chol) and palmitic acid (Palm) were covalently attached to the Cterminus of EK1 sequence under the help of a flexible polyethylene glycol (PEG) spacer, and the corresponding lipopeptides EK1C and EK1P were constructed, respectively ( Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, at the end of 2019, the outbreak of Wuhan pneumonia with an unknown etiological agent, the first Disease X following WHO's announcement was reported to WHO. Shortly thereafter, a novel coronavirus, SARS-CoV-2 (also known as 2019-nCoV or HCoV- 19), was identified to be the etiology of the Wuhan pneumonia, i.e., COVID-19 as designated by WHO.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Xia

Liu

Wang³

et al. 2020

Cell Res

1,195

1,420

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The recent outbreak of coronavirus disease 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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Xia

Liu

Wang³

et al. 2020

Cell Res

1,195

1,420

View full text Add to dashboard Cite

show abstract

“…Clinical examinations were performed on 0, 1, 3,5,8,15,19,23,28,35,42,50,63, and 92 dpi. On examination days, clinical parameters such as bodyweight, respiration rate, and oxygen saturation (SPO 2 ), as well as a blood sample and oral and nasal swabs, were collected.…”

Section: Methodsmentioning

confidence: 99%

“…Favipiravir protected hamsters from lethal Nipah virus Malaysia infection when treatment was administered orally or subcutaneously immediately after inoculation and continued for 13 days (4). Fusion inhibitory lipopeptides were shown to reduce mortality by 33% in the African green monkey (AGM) model of Nipah virus disease when administered daily from 1 day before until 5 days after inoculation with Nipah virus Malaysia (5). To date, only monoclonal antibody m102.4 treatment has shown efficacy in nonhuman primates when administered therapeutically (6,7).…”

Section: Introductionmentioning

confidence: 99%

Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

et al. 2019

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Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.

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“…Its mortality varies as per the outbreak and till date there is no inhibitors of NiV due to the constraints of being BSL4 pathogen. In literature few studies have been done regarding the development of inhibitors (Dawes et al, 2018;Mathieu et al, 2018). In the current study, we identified the DEGs among two different studies and tried to find out the common and different genes, which are up and down regulated.…”

Section: Discussionmentioning

confidence: 99%

Comparison of expression profiling through microarray and RNA-seq analysis for Nipah virus

Rajput

Kumar

2019

Preprint

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The Nipah virus is responsible various outbreaks among countries of south east Asia, most recent is in Kerala, India. It is considered to be highly contagious and having a range of vectors for transmission. The condition worsens due to the lack of effective inhibitors. This study is first study, which focused to detect the differentially expressed genes among two different NiV studies from 2012 and 2017. The transcriptomic profiling data were retrieved from the sequence archives. The multivariate gene enrichment analyses were performed on the log transformed data from them using pathway, gene ontology, disease, reactome, etc. The comparison study suggests that the down regulated differentially expressed genes are common among them as compared to up regulated ones with statistical significance. However, among the diseased category the upregulated genes are mostly from metabolic pathways and diseased category like metabolic pathways, heart failure, cholesterol metabolism while the downregulated genes linked to various cancers, and viral diseases like hepatitis, dengue, influenza, etc. We found various small molecules mapped in the pathways which are differentially expressed among the studies, which could be targeted so as to control the Nipah infection. In order to design the inhibitors, our study would be useful to extract the effective and broad-spectrum drug targets.

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Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates

Cited by 46 publications

References 46 publications

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

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

Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Comparison of expression profiling through microarray and RNA-seq analysis for Nipah virus

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