Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

Torres, Jaume; Surya, Wahyu; Li, Yan; Liu, Ding Xiang

doi:10.3390/v7062750

Cited by 25 publications

(28 citation statements)

References 171 publications

(232 reference statements)

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“…The E protein, also a viroporin 19 , was previously confirmed as a determinant of pathogenicity 4,5 in SARS-CoV-1. Protein E was used as target for SARS antivirals 6 , and studies using SARS-CoV with lacking or mutated protein E as vaccine candidates showed promising results [20][21][22][23] . Furthermore, the E gene is one of the key genes used in identification of SARS-CoV-2 through RT-PCR 7,24 .…”

Section: Resultsmentioning

confidence: 99%

Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

Álam

Kamau

Kulmanov

et al. 2020

Preprint

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The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells 1 . The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-2 3 . Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS) 4-6 , the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7,8 . However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride 9,10 ) or the PBM (SB203580 5 ), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.

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Section: Resultsmentioning

confidence: 99%

Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

Álam

Kamau

Kulmanov

et al. 2020

Preprint

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“…3 Alignment of deduced SH protein sequences. Dashed line, solid black line and blue line rectangles indicate 10 residue-long conserved fragment in the cytoplasmic domain Torres et al [ 32 ], transmembrane region Li et al [ 30 ] and a putative antigenic site, respectively. Asterisk shows the position of stop codons; − indicates gap.…”

Section: Resultsmentioning

confidence: 99%

Variability analysis and inter-genotype comparison of human respiratory syncytial virus small hydrophobic gene

Ivancic-Jelecki

Slović

Ljubin‐Sternak

et al. 2018

Virol J

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BackgroundSmall hydrophobic (SH) gene is one of the mostly diverse genomic regions of human respiratory syncytial virus (HRSV). Its coding region constitutes less than 50% of the complete gene length, enabling SH gene to be highly variable and the SH protein highly conserved. In standard HRSV molecular epidemiology studies, solely sequences of the second hypervariable region of the glycoprotein gene (HVR2) are analyzed. To what extent do the strains identical in HVR2 differ elsewhere in genomes is rarely investigated. Our goal was to investigate whether diversity and inter-genotype differences observed for HVR2 are also present in the SH gene.MethodsWe sequenced 198 clinical samples collected within a limited area and time frame. In this HRSV collection, rapid and significant changes in HVR2 occurred.ResultsOver 20% of strains from this pool (containing HRSV genotypes NA1, ON1, GA5, BA9 and BA10) would be incorrectly assumed to be identical to another strain if only the HVR2 region was analysed. The majority of differences found in SH gene were located in the 5′ untranslated region (UTR). Seven indels were detected, one was genotype GA5 specific. An in-frame deletion of 9 nucleotides (coding for amino acids 49–51) was observed in one of group A strains. Fifteen different SH protein sequences were detected; 68% of strains possessed the consensus sequence and most of others differed from the consensus in only one amino acid (only 4 strains differed in 2 amino acids). The majority of differing amino acids in group A viruses had the same identity as the corresponding amino acids in group B strains. When analysis was restricted to strains with identical HVR2 nucleotide sequences and differing SH protein sequences, 75% of differences observed in the SH ectodomain were located within region coding for amino acids 49–51.ConclusionsBasing HRSV molecular epidemiology studies solely on HVR2 largely underestimates the complexity of circulating virus populations. In strain identification, broadening of the genomic target sequence to SH gene would provide a more comprehensive insight into viral pool versatility and its evolutionary processes.Electronic supplementary materialThe online version of this article (10.1186/s12985-018-1020-9) contains supplementary material, which is available to authorized users.

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“…Interestingly, mutation of N15A and V25F, respectively, appear to hamper the oligomerisation of CoV E, at least to some extent. The appearance of monomers in response to V25F clearly suggests that this residues plays a more crucial role in oligomerisation, as opposed to N15A, which appears to reduce the amount of pentamers only slightly [139]. The ability of CoV E to assemble into homopentameric structures is clearly important in the formation of a functional CoV E viroporin [75,76,[135][136][137][138]140].…”

Section: Envelope and Envelope Proteinsmentioning

confidence: 98%

Coronavirus envelope protein: current knowledge

Schoeman

Fielding

2019

Virol J

1,828

1,859

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Background Coronaviruses (CoVs) primarily cause enzootic infections in birds and mammals but, in the last few decades, have shown to be capable of infecting humans as well. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and, more recently, Middle-East respiratory syndrome (MERS) has demonstrated the lethality of CoVs when they cross the species barrier and infect humans. A renewed interest in coronaviral research has led to the discovery of several novel human CoVs and since then much progress has been made in understanding the CoV life cycle. The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis. Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins. Main body This review aims to establish the current knowledge on CoV E by highlighting the recent progress that has been made and comparing it to previous knowledge. It also compares E to other viral proteins of a similar nature to speculate the relevance of these new findings. Good progress has been made but much still remains unknown and this review has identified some gaps in the current knowledge and made suggestions for consideration in future research. Conclusions The most progress has been made on SARS-CoV E, highlighting specific structural requirements for its functions in the CoV life cycle as well as mechanisms behind its pathogenesis. Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates. The high mortality rate of certain CoVs, along with their ease of transmission, underpins the need for more research into CoV molecular biology which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.

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Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

Cited by 25 publications

References 171 publications

Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

Variability analysis and inter-genotype comparison of human respiratory syncytial virus small hydrophobic gene

Coronavirus envelope protein: current knowledge

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