Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

Plewe, Michael; Sokolova, N. V.; Gantla, Vidyasagar Reddy; Brown, Eric; Naik, Shibani; Fetsko, Alexandra; Lorimer, Donald D.; Dranow, David M.; Smutney, Hayden; Bullen, Jameson; Sidhu, Rana; Master, Arshil; Wang, Junru; Kallel, E. Adam; Zhang, Lihong; Kalveram, Birte; Freiberg, Alexander N.; Henkel, Greg; McCormack, Ken

doi:10.1021/acsmedchemlett.0c00025

Cited by 14 publications

(20 citation statements)

References 17 publications

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“…Under the used reaction conditions products are less involved into the further oxidative transformations. This is in contrast to the results of reactions employing conventional catalysts [4,5].…”

Section: Resultscontrasting

confidence: 68%

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Synthesis of 4-(1-Adamantyl)-1-Naphthol and 4-(1-Adamantyl)-1-Methoxynaphthalene

Kondrasenko

Peterson

Rubaylo

2020

Journal of Siberian Federal University. Chemistry

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Section: Resultscontrasting

confidence: 68%

“…Combined aromatic core and adamantane moiety often pose as structural elements in promising antivirus compounds or functional materials [4][5][6]. Earlier we have reported the method of preparation of 2-(adamant-1-yl)-1-hydroxynaphthalene in reaction of 1-naphthol and 1-adamantanol in the mixture of chloroform and trifluoroacetic acid [7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4-(1-Adamantyl)-1-Naphthol and 4-(1-Adamantyl)-1-Methoxynaphthalene

Kondrasenko

Peterson

Rubaylo

2020

Journal of Siberian Federal University. Chemistry

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“…The W288 site is situated in a lesser ordered region of the glycan cap (the β17-β18 loop) just before the start of the MLD, which is deleted in the constructs of most structural studies. While most available GP structures do not model the corresponding region, we identified a set of 12 deposited isomorphic GP crystal structures of HEK293-derived material with electron density for W288 and its adjacent residues [41–45]. The individual crystal structures did not show a clear F o -F c density corresponding to the C2-linked mannose, but after averaging all available electron density maps, a clear ring structure did appear.…”

Section: Resultsmentioning

confidence: 99%

Glycan shield of the ebolavirus envelope glycoprotein GP

Peng

Rayaprolu

Parvate

et al. 2022

Preprint

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The envelope glycoprotein GP of the ebolaviruses is essential for host cell attachment and entry. It is also the primary target of the protective and neutralizing antibody response in both natural infection and vaccination. GP is heavily glycosylated with up to 17 predicted N-linked sites, numerous O-linked glycans in its disordered mucin-like domain (MLD), and three predicted C-linked mannosylation sites. Glycosylation of GP is important for host cell attachment to cell-surface lectins, as well as GP stability and fusion activity. Moreover, it has been shown to shield GP from neutralizing activity of serum antibodies. Here, we use mass spectrometry-based glycoproteomics to profile the site-specific glycosylation patterns of ebolavirus GP. We detect up to 16 unique O-linked glycosylation sites in the mucin-like domain, as well as two O-linked sites in the head and glycan cap domains of the receptor-binding GP1 subunit. Multiple O-linked glycans are observed at the S/T residues of N-linked glycosylation sequons, suggesting possible crosstalk between the two types of modifications. We also confirmed the presence of C-mannosylation at W288 in the context of trimeric GP. We find heterogenous, complex N-linked glycosylation at the majority of predicted sites as expected. By contrast, the two conserved sites N257 and N563 are enriched in unprocessed high-mannose and hybrid glycans, suggesting a role in host-cell attachment via DC-SIGN/L-SIGN. We discuss our findings in the context of antibody recognition to show how glycans contribute to and restrict neutralization epitopes. This information on how N-, O-, and C-linked glycans together build the heterogeneous glycan shield of GP can guide future immunological studies and functional interpretation of ebolavirus GP-antibody interactions.

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“…In the present study we instead followed the structurebased approach that led to recent advances in vaccine development for two distinct pathogens, RSV and HIV, which have yielded promising results in terms of induction of neutralizing antibodies when the relevant surface GPs were engineered to present a native-like pre-fusion conformation (35)(36)(37). Similar approaches were also applied for the production of EBOV GP trimers to be used mainly for structural biology studies aimed to investigate the formation of complexes between GP and neutralizing antibodies (12,38) or other therapeutic molecules (26,39). With these results as a proof-of-concept, we aimed at the production of a stabilized and soluble native-like EBOV GP trimer.…”

Section: Discussionmentioning

confidence: 99%

Designs and Characterization of Subunit Ebola GP Vaccine Candidates: Implications for Immunogenicity

Agnolon

Kiseljak²,

Wurm³

et al. 2020

Front. Immunol.

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The humoral responses of Ebola virus (EBOV) survivors mainly target the surface glycoprotein GP, and anti-GP neutralizing antibodies have been associated with protection against EBOV infection. In order to elicit protective neutralizing antibodies through vaccination a native-like conformation of the antigen is required. We therefore engineered and expressed in CHO cells several GP variants from EBOV (species Zaire ebolavirus , Mayinga variant), including a soluble GP ΔTM, a mucin-like domain-deleted GP ΔTM-ΔMUC, as well as two GP ΔTM-ΔMUC variants with C-terminal trimerization motifs in order to favor their native trimeric conformation. Inclusion of the trimerization motifs resulted in proteins mimicking GP metastable trimer and showing increased stability. The mucin-like domain appeared not to be critical for the retention of the native conformation of the GP protein, and its removal unmasked several neutralizing epitopes, especially in the trimers. The soluble GP variants inhibited mAbs neutralizing activity in a pseudotype transduction assay, further confirming the proteins’ structural integrity. Interestingly, the trimeric GPs, a native-like GP complex, showed stronger affinity for antibodies raised by natural infection in EBOV disease survivors rather than for antibodies raised in volunteers that received the ChAd3-EBOZ vaccine. These results support our hypothesis that neutralizing antibodies are preferentially induced when using a native-like conformation of the GP antigen. The soluble trimeric recombinant GP proteins we developed represent a novel and promising strategy to develop prophylactic vaccines against EBOV and other filoviruses.

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Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

Cited by 14 publications

References 17 publications

Synthesis of 4-(1-Adamantyl)-1-Naphthol and 4-(1-Adamantyl)-1-Methoxynaphthalene

Synthesis of 4-(1-Adamantyl)-1-Naphthol and 4-(1-Adamantyl)-1-Methoxynaphthalene

Glycan shield of the ebolavirus envelope glycoprotein GP

Designs and Characterization of Subunit Ebola GP Vaccine Candidates: Implications for Immunogenicity

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