RESUMEN
Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.
Asunto(s)
Fármacos Anti-VIH/química , Péptidos de Penetración Celular/química , Cloroquina/química , Secuencia de Aminoácidos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/toxicidad , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Péptidos de Penetración Celular/síntesis química , Cloroquina/toxicidad , VIH-1/fisiología , Humanos , Datos de Secuencia Molecular , Proteínas de la Matriz Viral/química , Internalización del Virus/efectos de los fármacosRESUMEN
Compounds which inhibit the HIV-1 replication cycle have been found amongst fragment peptides derived from an HIV-1 matrix (MA) protein. Overlapping peptide libraries covering the whole sequence of MA were designed and constructed with the addition of an octa-arginyl group to increase their cell membrane permeability. Imaging experiments with fluorescent-labeled peptides demonstrated these peptides with an octa-arginyl group can penetrate cell membranes. The fusion of an octa-arginyl group was proven to be an efficient way to find active peptides in cells such as HIV-inhibitory peptides.