Synthesis and Conformational Analysis of a Natural Peptide Inhibitor of HIV-1 Integrase

摘要

Integramide A, an effective inhibitor of the coupled reaction of HIV-1 integrase, is a 16-mer linear peptide characterized by nine C~α-methylated a-amino acids [five Iva, isovaline, and four Aib, a-aminoisobutyric acid, residues (Figure 1)] that was isolated from fungal extracts of Dendrodochium sp. The amino acid sequence was fully elucidated by the Merck group a few years ago [1]. On the other hand, the chiral sequence was only partially determined. In particular, the precise stereochemistry of the Iva~(14)-Iva~(15) dipeptide (known to contain one D- and one L-residue) near the C-terminus was not reported. We solved this unsettled issue by performing via solution methods the total chemical independent syntheses of both L-D and D-L 16-mer diastereomers and compared their chromatographic and spectroscopic properties with those of the natural inhibitor [2].