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-Iva(14)-D-Iva(15). Herein, we describe the syntheses of the natural compound and its D-Iva(14)-L-Iva(15) 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.
De Zotti
Marta
M
Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry University of Padova via Marzolo 1, 35131 Padova, Italy.
Damato
Francesca
F
Formaggio
Fernando
F
Crisma
Marco
M
Schievano
Elisabetta
E
Mammi
Stefano
S
Kaptein
Bernard
B
Broxterman
Quirinus B
QB
Felock
Peter J
PJ
Hazuda
Daria J
DJ
Singh
Sheo B
SB
Kirschbaum
Jochen
J
Brückner
Hans
H
Toniolo
Claudio
C
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D004151:Dipeptides / Q000737:chemistry*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D004151:Dipeptides; D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C456979:integramide A; D019427:HIV Integrase