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  1. Article ; Online: HIV-1 prehairpin intermediate inhibitors show efficacy independent of neutralization tier.

    Bell, Benjamin N / Bruun, Theodora U J / Friedland, Natalia / Kim, Peter S

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 8, Page(s) e2215792120

    Abstract: HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1-infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization ... ...

    Abstract HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1-infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the prehairpin intermediate, is not well understood. Here, we show that two inhibitors targeting distinct highly conserved regions of the prehairpin intermediate have strikingly consistent neutralization potencies (within ~100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the prehairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
    MeSH term(s) Humans ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies ; HIV Infections/drug therapy ; HIV-1/drug effects ; Neutralization Tests
    Chemical Substances Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies
    Language English
    Publishing date 2023-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2215792120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  2. Article ; Online: Neutralizing antibodies targeting the SARS-CoV-2 receptor binding domain isolated from a naïve human antibody library.

    Bell, Benjamin N / Powell, Abigail E / Rodriguez, Carlos / Cochran, Jennifer R / Kim, Peter S

    Protein science : a publication of the Protein Society

    2021  Volume 30, Issue 4, Page(s) 716–727

    Abstract: Infection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently ... ...

    Abstract Infection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS-CoV-2 neutralizing antibodies. Here, we used a yeast surface-display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS-CoV-2 spike-pseudotyped lentivirus with IC
    MeSH term(s) Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/metabolism ; Binding Sites ; COVID-19/metabolism ; Epitopes/chemistry ; Epitopes/metabolism ; Humans ; Molecular Docking Simulation ; Protein Binding ; Protein Interaction Domains and Motifs ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism
    Chemical Substances Antibodies, Neutralizing ; Epitopes ; 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)
    Language English
    Publishing date 2021-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.4044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors.

    Weidenbacher, Payton A-B / Waltari, Eric / de Los Rios Kobara, Izumi / Bell, Benjamin N / Morris, Mary Kate / Cheng, Ya-Chen / Hanson, Carl / Pak, John E / Kim, Peter S

    Nature chemical biology

    2022  Volume 18, Issue 11, Page(s) 1270–1276

    Abstract: Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. ... ...

    Abstract Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
    MeSH term(s) Humans ; Angiotensin-Converting Enzyme 2 ; SARS-CoV-2 ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus/metabolism ; Antibodies, Viral/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Epitopes ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Biological Products ; COVID-19 Drug Treatment
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Epitopes ; Antibodies, Monoclonal ; Biological Products ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-09-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-022-01140-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6251: Show issues Location:
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  4. Article ; Online: A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity.

    Rubio, Adonis A / Filsinger Interrante, Maria V / Bell, Benjamin N / Brown, Clayton L / Bruun, Theodora U J / LaBranche, Celia C / Montefiori, David C / Kim, Peter S

    Journal of virology

    2021  Volume 95, Issue 15, Page(s) e0235020

    Abstract: HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 ... ...

    Abstract HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date, these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5's six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in the 50% inhibitory dose (ID
    MeSH term(s) Anti-HIV Agents/pharmacology ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Cell Line ; Enfuvirtide/pharmacology ; HEK293 Cells ; HIV Envelope Protein gp41/antagonists & inhibitors ; HIV Envelope Protein gp41/immunology ; HIV Infections/immunology ; HIV Infections/prevention & control ; HIV-1/immunology ; Humans ; Protein Domains/immunology
    Chemical Substances Anti-HIV Agents ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; HIV Envelope Protein gp41 ; gp41 protein, Human immunodeficiency virus 1 ; Enfuvirtide (19OWO1T3ZE)
    Language English
    Publishing date 2021-07-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.02350-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 609: Show issues Location:
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  5. Article ; Online: Crystal structure of AdoMet radical enzyme 7-carboxy-7-deazaguanine synthase from Escherichia coli suggests how modifications near [4Fe-4S] cluster engender flavodoxin specificity.

    Grell, Tsehai A J / Bell, Benjamin N / Nguyen, Chi / Dowling, Daniel P / Bruender, Nathan A / Bandarian, Vahe / Drennan, Catherine L

    Protein science : a publication of the Protein Society

    2018  Volume 28, Issue 1, Page(s) 202–215

    Abstract: 7-Carboxy-7-deazaguanine synthase, QueE, catalyzes the radical mediated ring contraction of 6-carboxy-5,6,7,8-tetrahydropterin, forming the characteristic pyrrolopyrimidine core of all 7-deazaguanine natural products. QueE is a member of the S-adenosyl-L- ...

    Abstract 7-Carboxy-7-deazaguanine synthase, QueE, catalyzes the radical mediated ring contraction of 6-carboxy-5,6,7,8-tetrahydropterin, forming the characteristic pyrrolopyrimidine core of all 7-deazaguanine natural products. QueE is a member of the S-adenosyl-L-methionine (AdoMet) radical enzyme superfamily, which harnesses the reactivity of radical intermediates to perform challenging chemical reactions. Members of the AdoMet radical enzyme superfamily utilize a canonical binding motif, a CX
    MeSH term(s) Amino Acid Motifs ; Carbon-Nitrogen Lyases/chemistry ; Crystallography, X-Ray ; Escherichia coli/enzymology ; Escherichia coli Proteins/chemistry ; Flavodoxin ; Iron-Sulfur Proteins/chemistry ; Protein Domains ; Substrate Specificity
    Chemical Substances Escherichia coli Proteins ; Flavodoxin ; Iron-Sulfur Proteins ; Carbon-Nitrogen Lyases (EC 4.3.-)
    Language English
    Publishing date 2018-10-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.3529
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3407: Show issues Location:
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    Zs.MO 1: Show issues

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  6. Article ; Online: The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.

    Montefiori, David C / Filsinger Interrante, Maria V / Bell, Benjamin N / Rubio, Adonis A / Joyce, Joseph G / Shiver, John W / LaBranche, Celia C / Kim, Peter S

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 118, Issue 3

    Abstract: The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug ...

    Abstract The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)
    MeSH term(s) Amino Acid Sequence ; Animals ; Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/pharmacology ; Antibody Affinity ; Guinea Pigs ; HIV Antibodies/immunology ; HIV Antibodies/pharmacology ; HIV Envelope Protein gp41/genetics ; HIV Envelope Protein gp41/immunology ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/virology ; HIV Seropositivity/immunology ; HIV-1/drug effects ; HIV-1/immunology ; HIV-1/pathogenicity ; Humans ; Immune Sera/immunology ; Immune Sera/pharmacology ; Immunization ; Immunoglobulin G/immunology ; Receptors, IgG/immunology ; Repetitive Sequences, Amino Acid/genetics ; Repetitive Sequences, Amino Acid/immunology ; Virus Internalization/drug effects
    Chemical Substances Antibodies, Neutralizing ; HIV Antibodies ; HIV Envelope Protein gp41 ; Immune Sera ; Immunoglobulin G ; Receptors, IgG
    Language English
    Publishing date 2020-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2018027118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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