RESUMEN
Feglymycin (FGM), a natural Streptomyces-derived 13mer peptide, consistently inhibits HIV replication in the lower µM range. FGM also inhibits HIV cell-to-cell transfer between HIV-infected T cells and uninfected CD4(+) T cells and the DC-SIGN-mediated viral transfer to CD4(+) T cells. FGM potently interacts with gp120 (X4 and R5) as determined by SPR analysis and shown to act as a gp120/CD4 binding inhibitor. Alanine-scan analysis showed an important role for l-aspartic acid at position 13 for its anti-HIV activity. In vitro generated FGM-resistant HIV-1 IIIB virus (HIV-1 IIIB(FGMres)) showed two unique mutations in gp120 at positions I153L and K457I. HIV-1 IIIB(FGMres) virus was equally susceptible to other viral binding/adsorption inhibitors with the exception of dextran sulfate (9-fold resistance) and cyclotriazadisulfonamide (>15-fold), two well-described compounds that interfere with HIV entry. In conclusion, FGM is a unique prototype lead peptide with potential for further development of more potent anti-HIV derivatives.
Asunto(s)
Fármacos Anti-VIH/farmacología , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Proteínas/farmacología , Internalización del Virus/efectos de los fármacos , Secuencia de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacología , Fármacos Anti-VIH/química , Proteínas Bacterianas/química , Proteínas Bacterianas/farmacología , Antígenos CD4/efectos de los fármacos , Línea Celular , Descubrimiento de Drogas , Células Gigantes/efectos de los fármacos , VIH-1/clasificación , VIH-1/patogenicidad , VIH-1/fisiología , Humanos , Péptidos , Proteínas/químicaRESUMEN
An adaptable approach: The first highly convergent stereoselective synthesis of feglymycin (see structure) and its enantiomer is based on the coupling of repeating peptide fragments. The use of weakly basic conditions throughout the synthesis suppressed the epimerization of sensitive aryl glycine units. Feglymycin has strong anti-HIV activity as well as potent (previously identified as weak) antibacterial activity against Staphylococcus aureus.