RESUMEN
The bioorganic synthesis of an end-capped anti-HIV peptide from a recombinant protein was investigated. Cyanogen bromide-mediated cleavage of two Met-Gln sites across the target anti-HIV sequence generated an HIV-1 fusion inhibitor (SC35EK) analog bearing an N-terminal pyroglutamate (pGlu) residue and a C-terminal homoserine lactone (Hsl) residue. The end-capped peptide, pGlu-SC35EK-Hsl, had similar bioactivity and biophysical properties to the parent peptide, and an improved resistance to peptidase-mediated degradation was observed compared with the non-end-capped peptide obtained using standard recombinant technology.
Asunto(s)
4-Butirolactona/análogos & derivados , Inhibidores de Fusión de VIH/síntesis química , VIH-1/efectos de los fármacos , Ácido Pirrolidona Carboxílico/síntesis química , 4-Butirolactona/síntesis química , 4-Butirolactona/química , 4-Butirolactona/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , Células HeLa , Humanos , Ratones , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacología , Proteínas Recombinantes/síntesis química , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Bioorganic synthesis of N- and C-terminal end-capped peptides by two simultaneous S-cyanocysteine-mediated cleavages of recombinant proteins is described. This approach is demonstrated in the preparation of anti-HIV fusion inhibitory peptides.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Cisteína/química , Inhibidores de Fusión de VIH/síntesis química , Péptidos/síntesis química , Proteínas Recombinantes de Fusión/metabolismo , Secuencia de Aminoácidos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , Humanos , Datos de Secuencia Molecular , Péptidos/química , Péptidos/farmacologíaRESUMEN
Emergence of multi-drug resistant HIV-1 is a serious problem for AIDS treatment. Recently, the virus-cell membrane fusion process has been identified as a promising target for the development of novel drugs against these resistant variants. In this study, we identified a 29-residue peptide fusion inhibitor, SC29EK, which shows activity comparable to the previously reported inhibitor SC35EK. Some residues in SC29EK not required for interaction with virus gp41 heptad repeat 1 (HR1) were replaced with a non-proteinogenic amino acid, 2-aminoisobutyric acid (Aib), to stabilize the alpha-helix structure and to provide resistance to peptidases.