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  1. Article: The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2.

    Procko, Erik

    bioRxiv : the preprint server for biology

    2020  

    Abstract: The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 ... ...

    Abstract The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic, prophylactic and diagnostic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding domain of S. Mutations are found across the interface, in the N90-glycosylation motif, and at buried sites where they are predicted to enhance local folding and presentation of the interaction epitope. When single substitutions are combined, large increases in binding can be achieved. The mutational landscape offers a blueprint for engineering high affinity proteins and peptides that block receptor binding sites on S to meet this unprecedented challenge.
    Keywords covid19
    Language English
    Publishing date 2020-05-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2020.03.16.994236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Deep mutagenesis in the study of COVID-19: a technical overview for the proteomics community.

    Procko, Erik

    Expert review of proteomics

    2020  Volume 17, Issue 9, Page(s) 633–638

    Abstract: Introduction: The spike (S) of SARS coronavirus 2 (SARS-CoV-2) engages angiotensin-converting enzyme 2 (ACE2) on a host cell to trigger viral-cell membrane fusion and infection. The extracellular region of ACE2 can be administered as a soluble decoy to ... ...

    Abstract Introduction: The spike (S) of SARS coronavirus 2 (SARS-CoV-2) engages angiotensin-converting enzyme 2 (ACE2) on a host cell to trigger viral-cell membrane fusion and infection. The extracellular region of ACE2 can be administered as a soluble decoy to compete for binding sites on the receptor-binding domain (RBD) of S, but it has only moderate affinity and efficacy. The RBD, which is targeted by neutralizing antibodies, may also change and adapt through mutation as SARS-CoV-2 becomes endemic, posing challenges for therapeutic and vaccine development.
    Areas covered: Deep mutagenesis is a Big Data approach to characterizing sequence variants. A deep mutational scan of ACE2 expressed on human cells identified mutations that increase S affinity and guided the engineering of a potent and broad soluble receptor decoy. A deep mutational scan of the RBD displayed on the surface of yeast has revealed residues tolerant of mutational changes that may act as a source for drug resistance and antigenic drift.
    Expert opinion: Deep mutagenesis requires a selection of diverse sequence variants; an in vitro evolution experiment that is tracked with next-generation sequencing. The choice of expression system, diversity of the variant library and selection strategy have important consequences for data quality and interpretation.
    MeSH term(s) Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Binding Sites ; Mutagenesis ; Mutation ; Protein Interaction Domains and Motifs ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-10-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2299100-1
    ISSN 1744-8387 ; 1478-9450
    ISSN (online) 1744-8387
    ISSN 1478-9450
    DOI 10.1080/14789450.2020.1833721
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  3. Article ; Online: The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2

    Erik Procko

    Abstract: SUMMARYThe rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency, and no approved therapeutics or vaccines are currently available. The viral spike protein S binds ACE2 on host cells to initiate ... ...

    Abstract SUMMARYThe rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency, and no approved therapeutics or vaccines are currently available. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic and prophylactic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding domain of S at a cell surface. Mutations are found across the interface and also at buried sites where they are predicted to enhance folding and presentation of the interaction epitope. The N90-glycan on ACE2 hinders association. The mutational landscape offers a blueprint for engineering high affinity ACE2 receptors to meet this unprecedented challenge.
    Keywords covid19
    Publisher biorxiv
    Document type Article ; Online
    DOI 10.1101/2020.03.16.994236
    Database COVID19

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  4. Article ; Online: Deep mutagenesis in the study of COVID-19

    Procko, Erik

    Expert Review of Proteomics

    a technical overview for the proteomics community

    2020  , Page(s) 1–6

    Keywords Biochemistry ; Molecular Biology ; covid19
    Language English
    Publisher Informa UK Limited
    Publishing country uk
    Document type Article ; Online
    ZDB-ID 2299100-1
    ISSN 1744-8387 ; 1478-9450
    ISSN (online) 1744-8387
    ISSN 1478-9450
    DOI 10.1080/14789450.2020.1833721
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6686: Show issues Location:
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  5. Article ; Online: The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2

    Procko, Erik

    bioRxiv

    Abstract: The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency, and no approved therapeutics or vaccines are currently available. The viral spike protein S binds ACE2 on host cells to initiate molecular ... ...

    Abstract The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency, and no approved therapeutics or vaccines are currently available. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic and prophylactic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding domain of S at a cell surface. Mutations are found across the interface and also at buried sites where they are predicted to enhance folding and presentation of the interaction epitope. The N90-glycan on ACE2 hinders association. The mutational landscape offers a blueprint for engineering high affinity ACE2 receptors to meet this unprecedented challenge.
    Keywords covid19
    Language English
    Publishing date 2020-03-17
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.03.16.994236
    Database COVID19

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  6. Article: Deep mutagenesis in the study of COVID-19: a technical overview for the proteomics community

    Procko, Erik

    Expert Rev Proteomics

    Abstract: INTRODUCTION: The spike (S) of SARS coronavirus 2 (SARS-CoV-2) engages angiotensin-converting enzyme 2 (ACE2) on a host cell to trigger viral-cell membrane fusion and infection. The extracellular region of ACE2 can be administered as a soluble decoy to ... ...

    Abstract INTRODUCTION: The spike (S) of SARS coronavirus 2 (SARS-CoV-2) engages angiotensin-converting enzyme 2 (ACE2) on a host cell to trigger viral-cell membrane fusion and infection. The extracellular region of ACE2 can be administered as a soluble decoy to compete for binding sites on the receptor-binding domain (RBD) of S, but it has only moderate affinity and efficacy. The RBD, which is targeted by neutralizing antibodies, may also change and adapt through mutation as SARS-CoV-2 becomes endemic, posing challenges for therapeutic and vaccine development. AREAS COVERED: Deep mutagenesis is a Big Data approach to characterizing sequence variants. A deep mutational scan of ACE2 expressed on human cells identified mutations that increase S affinity and guided the engineering of a potent and broad soluble receptor decoy. A deep mutational scan of the RBD displayed on the surface of yeast has revealed residues tolerant of mutational changes that may act as a source for drug resistance and antigenic drift. EXPERT OPINION: Deep mutagenesis requires a selection of diverse sequence variants; an in vitro evolution experiment that is tracked with next-generation sequencing. The choice of expression system, diversity of the variant library and selection strategy have important consequences for data quality and interpretation.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #883035
    Database COVID19

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  7. Article: Deep Mutational Scanning of Viral Glycoproteins and Their Host Receptors.

    Narayanan, Krishna K / Procko, Erik

    Frontiers in molecular biosciences

    2021  Volume 8, Page(s) 636660

    Abstract: Deep mutational scanning or deep mutagenesis is a powerful tool for understanding the sequence diversity available to viruses for adaptation in a laboratory setting. It generally involves tracking ... ...

    Abstract Deep mutational scanning or deep mutagenesis is a powerful tool for understanding the sequence diversity available to viruses for adaptation in a laboratory setting. It generally involves tracking an
    Language English
    Publishing date 2021-04-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2021.636660
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  8. Article ; Online: ACE2-based decoy receptors for SARS coronavirus 2.

    Jing, Wenyang / Procko, Erik

    Proteins

    2021  Volume 89, Issue 9, Page(s) 1065–1078

    Abstract: SARS coronavirus 2 is neutralized by proteins that block receptor-binding sites on spikes that project from the viral envelope. In particular, substantial research investment has advanced monoclonal antibody therapies to the clinic where they have shown ... ...

    Abstract SARS coronavirus 2 is neutralized by proteins that block receptor-binding sites on spikes that project from the viral envelope. In particular, substantial research investment has advanced monoclonal antibody therapies to the clinic where they have shown partial efficacy in reducing viral burden and hospitalization. An alternative is to use the host entry receptor, angiotensin-converting enzyme 2 (ACE2), as a soluble decoy that broadly blocks SARS-associated coronaviruses with limited potential for viral escape. Here, we summarize efforts to engineer higher affinity variants of soluble ACE2 that rival the potency of affinity-matured antibodies. Strategies have also been used to increase the valency of ACE2 decoys for avid spike interactions and to improve pharmacokinetics via IgG fusions. Finally, the intrinsic catalytic activity of ACE2 for the turnover of the vasoconstrictor angiotensin II may directly address COVID-19 symptoms and protect against lung and cardiovascular injury, conferring dual mechanisms of action unachievable by monoclonal antibodies. Soluble ACE2 derivatives therefore have the potential to be next generation therapeutics for addressing the immediate needs of the current pandemic and possible future outbreaks.
    MeSH term(s) Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Humans ; Immunoglobulin Fc Fragments/chemistry ; Immunoglobulin Fc Fragments/metabolism ; Molecular Mimicry ; Mutation ; Nanoparticles/chemistry ; Nanoparticles/metabolism ; Protein Binding ; Receptors, Virus/chemistry ; Receptors, Virus/metabolism ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; SARS-CoV-2/chemistry ; SARS-CoV-2/metabolism
    Chemical Substances Immunoglobulin Fc Fragments ; Receptors, Virus ; Recombinant Fusion Proteins ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2021-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26140
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2291: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  9. Article ; Online: Machine Learning Guided Design of High-Affinity ACE2 Decoys for SARS-CoV-2 Neutralization.

    Chan, Matthew C / Chan, Kui K / Procko, Erik / Shukla, Diwakar

    The journal of physical chemistry. B

    2023  Volume 127, Issue 9, Page(s) 1995–2001

    Abstract: A potential therapeutic strategy for neutralizing SARS-CoV-2 infection is engineering high-affinity soluble ACE2 decoy proteins to compete for binding to the viral spike (S) protein. Previously, a deep mutational scan of ACE2 was performed and has led to ...

    Abstract A potential therapeutic strategy for neutralizing SARS-CoV-2 infection is engineering high-affinity soluble ACE2 decoy proteins to compete for binding to the viral spike (S) protein. Previously, a deep mutational scan of ACE2 was performed and has led to the identification of a triple mutant variant, named sACE2
    MeSH term(s) Humans ; SARS-CoV-2/genetics ; COVID-19 ; Angiotensin-Converting Enzyme 2 ; Algorithms ; Machine Learning ; Mutation ; Protein Binding
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2023-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.3c00469
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  10. Article ; Online: Structural Rearrangement of the Serotonin Transporter Intracellular Gate Induced by Thr276 Phosphorylation.

    Chan, Matthew C / Procko, Erik / Shukla, Diwakar

    ACS chemical neuroscience

    2022  Volume 13, Issue 7, Page(s) 933–945

    Abstract: The reuptake of the neurotransmitter serotonin from the synaptic cleft by the serotonin transporter, SERT, is essential for proper neurological signaling. Biochemical studies have shown that Thr276 of transmembrane helix 5 is a site of PKG-mediated SERT ... ...

    Abstract The reuptake of the neurotransmitter serotonin from the synaptic cleft by the serotonin transporter, SERT, is essential for proper neurological signaling. Biochemical studies have shown that Thr276 of transmembrane helix 5 is a site of PKG-mediated SERT phosphorylation, which has been proposed to shift the SERT conformational equilibria to promote inward-facing states, thus enhancing 5-HT transport. Recent structural and simulation studies have provided insights into the conformation transitions during substrate transport but have not shed light on SERT regulation via post-translational modifications. Using molecular dynamics simulations and Markov state models, we investigate how Thr276 phosphorylation impacts the SERT mechanism and its role in enhancing transporter stability and function. Our simulations show that Thr276 phosphorylation alters the hydrogen-bonding network involving residues on transmembrane helix 5. This in turn decreases the free energy barriers for SERT to transition to the inward-facing state, thus facilitating 5-HT import. The results provide atomistic insights into
    MeSH term(s) Biological Transport ; Molecular Dynamics Simulation ; Phosphorylation ; Serotonin/metabolism ; Serotonin Plasma Membrane Transport Proteins/metabolism
    Chemical Substances Serotonin Plasma Membrane Transport Proteins ; Serotonin (333DO1RDJY)
    Language English
    Publishing date 2022-03-08
    Publishing country United States
    Document type Journal Article
    ISSN 1948-7193
    ISSN (online) 1948-7193
    DOI 10.1021/acschemneuro.1c00714
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