Rationally designed interfacial peptides are efficient in vitro inhibitors of HIV-1 capsid assembly with antiviral activity
EntityUAM. Departamento de Biología Molecular
PublisherPublic Library of Science
10.1371/journal.pone.0023877Plos One 6.9 (2011): e23877
Funded byThis 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)
ProjectComunidad de Madrid. S2009/MAT-1467/NANOOBJETOS
SubjectsAnti-HIV Agents; Capsid; Peptide Fragments; Protein Structure; Amino Acid Sequence; Biología y Biomedicina / Biología
Rights© 2011 Bocanegra et al.
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
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
Google Scholar:Bocanegra, Rebeca - Nevot, María - Doménech, Rosa - López, Inmaculada - Abián, Olga - Rodríguez-Huete, Alicia - Cavasotto, Claudio N. - Velázquez-Campoy, Adrián - Gómez Escribano, Javier - Martínez, Miguel Ángel - Neira, José Luis - Mateu, Mauricio G.
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