ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

Braun, Maya; Sharon, Elad; Unterman, Irene; Miller, Maya; Shtern, Anna Mellul; Benenson, Shmuel; Vainstein, Alexander; Tabach, Yuval

doi:10.1016/j.isci.2020.101384

Cited by 16 publications

(15 citation statements)

References 47 publications

(62 reference statements)

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“…Additionally, a comprehensive evolutionary analysis of angiotensin-converting enzyme 2 (ACE2), the key receptor for SARS-CoV-2 entry mechanism to cell, identified that the protein is conserved across the majority of metazoan, suggesting that most metazoan is a potential reservoir for SARS-CoV-2. 29 Combined with the insight of the conservation of ACE2, our results on the evolutionary roots of genes in groups 2 and 3 suggest that the SARS-CoV-2 ability to hijack the glycosylation biosynthetic processes and ubiquitin-dependent ERAD pathway to mediate immune evasion may be conserved among metazoans. This phylogenetic profiling approach can also be used to predict the potential intermediate hosts of a viral pathogen by comparing the evolutionary roots of host cell receptor and host interactors of the essential protein of a viral pathogen.…”

Section: Discussionmentioning

confidence: 60%

The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling

Fahmi

Kitagawa

Yasui

et al. 2021

Evol Bioinform Online

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ORF8 is a highly variable genomic region of SARS-CoV-2. Although non-essential and the precise functions are unknown, it has been suggested that this protein assists in SARS-CoV-2 replication in the early secretory pathway and in immune evasion. We utilized the binding partners of SARS-CoV-2 proteins in human HEK293T cells and performed genome-wide phylogenetic profiling and clustering analyses in 446 eukaryotic species to predict and discover ORF8 binding partners that share associated functional mechanisms based on co-evolution. Results classified 47 ORF8 binding partner proteins into 3 clusters (groups 1-3), which were conserved in vertebrates (group 1), metazoan (group 2), and eukaryotes (group 3). Gene ontology analysis indicated that group 1 had no significant associated biological processes, while groups 2 and 3 were associated with glycoprotein biosynthesis process and ubiquitin-dependent endoplasmic reticulum-associated degradation pathways, respectively. Collectively, our results classified potential genes that might be associated with SARS-CoV-2 viral pathogenesis, specifically related to acute respiratory distress syndrome, and the secretory pathway. Here, we discuss the possible role of ORF8 in viral pathogenesis and in assisting viral replication and immune evasion via secretory pathway, as well as the possible factors associated with the rapid evolution of ORF8.

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Section: Discussionmentioning

confidence: 60%

The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling

Fahmi

Kitagawa

Yasui

et al. 2021

Evol Bioinform Online

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“…genes that are either conserved or lost as a group) are functionally related, often belonging to the same pathway (27)(28)(29)31). We have shown that both across-clade and within-clade measures of co-evolution can be informative (27,32,39), and thus we computed NPPs both across all eukaryotes ( Fig. 1A and Fig.…”

Section: Phylogenetic Profile Analysis Of Mecp2 In Eukaryotes and Mammentioning

confidence: 99%

Expanding theMECP2network using comparative genomics reveals potential therapeutic targets for Rett syndrome

Unterman

Bloch

Cazacu³

et al. 2021

Preprint

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Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appear to act on Nuclear Factor Kappa B (NF-κB) signalling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

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“…Molecular evolution studies and phylogenic analysis of SARS-CoV-2 and ACE2 strongly suggest that SARS-CoV-2 might have crossed the species-specific barrier, with pangolins representing an intermediate species and bat as the main reservoir [ 24 , 25 ]. ACE2 profiling and pattern conservation analysis have displayed that it is highly conserved within vertebrates, noting that this conservation shows high divergence as the evolutionary distance increases from Homo sapiens [ 26 ]. In addition, molecular characterization and sequence alignment analysis of ACE2 show that human and non-human primates display a low evolution rate with high similarity across species except for chicken [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Badawi

Ali

2021

Hum Genomics

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With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

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ACE2 Co-evolutionary Pattern Suggests Targets for Pharmaceutical Intervention in the COVID-19 Pandemic

Cited by 16 publications

References 47 publications

The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling

The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling

Expanding theMECP2network using comparative genomics reveals potential therapeutic targets for Rett syndrome

ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

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