Rationally designed interfacial peptides are efficient in vitro inhibitors of HIV-1 capsid assembly with antiviral activity
Entity
UAM. Departamento de Biología MolecularPublisher
Public Library of ScienceDate
2011-09-08Citation
10.1371/journal.pone.0023877
Plos One 6.9 (2011): e23877
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0023877Funded by
This work was supported by grants from Fundacion para la Investigacion y Prevencion del SIDA en ESpaña (FIPSE Exp: 36557/06) to MGM, JLN and MAM, Spain's Ministerio de Ciencia e Innovacion (BIO2009-10072 to MGM and SAF2008-05742-C02-01 and CSD20008-00005 to JLN and JG), Comunidad de Madrid (S-2009/MAT/1467 to MGM), Generalitat Valenciana (ACOMP2010/114 to JLN and JG). Short-term research of RD in AVC's laboratory was supported by Ministerio de Ciencia e Innovacion (BFU2008-02302-BMC)Project
Comunidad de Madrid. S2009/MAT-1467/NANOOBJETOSSubjects
Anti-HIV Agents; Capsid; Peptide Fragments; Protein Structure; Amino Acid Sequence; Biología y Biomedicina / BiologíaRights
© 2011 Bocanegra et al.Abstract
Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity
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Google Scholar:Bocanegra, Rebeca
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Nevot, María
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Doménech, Rosa
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López, Inmaculada
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Abián, Olga
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Rodríguez-Huete, Alicia
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Cavasotto, Claudio N.
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Velázquez-Campoy, Adrián
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Gómez Escribano, Javier
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Martínez, Miguel Ángel
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Neira, José Luis
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Mateu, Mauricio G.
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