Complete Absolute Configuration of Integramide A, a Natural, 16-mer Peptide Inhibitor of HIV-1 Integrase, Elucidated by Total Synthesis

That elusive chiral pair: The chiral sequence of the nonribosomal, linear, 16-mer peptide integramide A, an HIV-1 integrase A inhibitor, has been fully elucidated. Total independent chemical syntheses of two diastereomers of integramide A (L-Iva14-D-Iva15 and D-Iva14-L-Iva15) in the solution phase, combined with their HPLC and 1D- and 2D-NMR analyses, provide unambiguous evidence that the natural inhibitor has a previously unassigned L-Iva14-D-Iva15 chiral pair

SYNTHESIS AND CONFORMATIONAL ANALYSIS OF A NATURAL PEPTIDE INHIBITOR OF HIV-1 INTEGRASE

Integramide A is a 16-amino acid peptide inhibitor of the enzymeHIV-1 integrase. We have recently reported that the absolute stereochemistries of the dipeptide sequence near the C terminus are L-Iva14-D-Iva15. Herein, we describe the syntheses of the natural compound and its D-Iva14-L-Iva15 diastereomer, and the results of their chromatographic/mass spectrometric analyses. We present the conformational analysis of the two compounds and some of their synthetic intermediates of different main-chain length in the crystal state (by X-ray diffraction) and in solvents of different polarities (using circular dichroism, FTIR absorption, and 2D NMR techniques).These data shed light on the mechanism of inhibition of HIV-1 integrase, which is an important target for anti-HIV therapy

Total Synthesis, Characterization, and Conformational Analysis of the Naturally Occurring Hexadecapeptide Integramide A and a Diastereomer

Integramide A is a 16-amino acid peptide inhibitor of the enzyme HIV-1 integrase. We have recently reported that the absolute stereochemistries of the dipeptide sequence near the C terminus are L-Iva14-D-Iva15. Herein, we describe the syntheses of the natural compound and its D-Iva14-L-Iva15 diastereomer, and the results of their chromatographic/mass spectrometric analyses. We present the conformational analysis of the two compounds and some of their synthetic intermediates of different main-chain length in the crystal state (by X-ray diffraction) and in solvents of different polarities (using circular dichroism, FTIR absorption, and 2D NMR techniques). These data shed light on the mechanism of inhibition of HIV-1 integrase, which is an important target for anti-HIV therapy