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Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization

Identifieur interne : 003752 ( Main/Exploration ); précédent : 003751; suivant : 003753

Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization

Auteurs : Carl D. Elkin [États-Unis] ; Harmon J. Zuccola [États-Unis] ; James M. Hogle [États-Unis] ; Diane Joseph-Mccarthy [États-Unis]

Source :

Journal of Computer-Aided Molecular Design [ 0920-654X ] ; 2000-11-01.

RBID : ISTEX:C489559D93B9D694AB570E69C703A2A254D4A5B2

Descripteurs français

KwdFr :
- Algorithmes, Antigènes d'hépatite virale (), Antiviraux (), Antiviraux (pharmacologie), Conformation des protéines, Dimérisation, Systèmes de gestion de bases de données, Séquence d'acides aminés, Virus de l'hépatite delta (), Virus de l'hépatite delta (immunologie).
MESH :
- immunologie : Virus de l'hépatite delta.
- pharmacologie : Antiviraux.
- Algorithmes, Antigènes d'hépatite virale, Antiviraux, Conformation des protéines, Dimérisation, Systèmes de gestion de bases de données, Séquence d'acides aminés, Virus de l'hépatite delta.

English descriptors

KwdEn :
- Algorithms, Amino Acid Sequence, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Database Management Systems, Dimerization, Hepatitis Antigens (chemistry), Hepatitis Delta Virus (drug effects), Hepatitis Delta Virus (immunology), Protein Conformation, coiled-coil formation, d-peptide ligands, multiple copy simultaneous search (MCSS), structure-based drug design.
MESH :
- chemical , chemistry : Antiviral Agents, Hepatitis Antigens.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Hepatitis Delta Virus.
- immunology : Hepatitis Delta Virus.
- Algorithms, Amino Acid Sequence, Database Management Systems, Dimerization, Protein Conformation.

Abstract

Abstract: Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6 (1998) 821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the d-isomer of the target structure was selected as the template. Over 200 000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences, and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as d-peptides and docked with the l-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.

Url:

https://api.istex.fr/ark:/67375/VQC-WS2VWG99-R/fulltext.pdf

DOI: 10.1023/A:1008146015629

Affiliations:

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<front><div type="abstract" xml:lang="en">Abstract: Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6 (1998) 821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the d-isomer of the target structure was selected as the template. Over 200 000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences, and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as d-peptides and docked with the l-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.</div>
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Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization

Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

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