title: Triple Hyp→Pro replacement in integramide A, a peptaib inhibitor of HIV-1 integrase: Effect on conformation and bioactivity.
abstract: AIDS is produced by HIV-induced infections. HIV integrase is an important enzyme as it is critical for the integration of the HIV genome into that of the host cell. This complex process is exclusively carried out by a viral enzyme not found in the host cell. Therefore, this protein represents a safe target for the development of single or combined anti-HIV therapy. Integramide A is a 16-mer long, effective peptaib inhibitor of HIV-1 integrase. We have previously described a versatile synthetic strategy in solution to afford this natural compound and its diastereomer at positions 14 and 15. We also found that both peptides display a significant inhibitory activity. Here, we present our data on the synthesis in solution, in-depth conformational analysis, and biological activity against HIV-integrase of the analogs of the two above mentioned peptides in which all of the three (2S,4R)-Hyp residues at positions 2, 9, and 13 are replaced by L-Pro. This study definitely confirms that the mixed α-/3(10) - helical conformation of natural integramide A plays a key role in its mechanism of inhibition. Moreover, our data provide evidence that the amphipathic character of this helical structure is not required for the activity of integramide A against HIV-1 integrase. These observations will hopefully help us to further clarify the precise mechanism of inhibition of this interesting peptaib and to identify shorter peptide sequences active against HIV-1 integrase.
authors.affiliation: Department of Chemistry, University of Padova, Institute of Biomolecular Chemistry, CNR, Padova Unit, 35131 Padova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: De Zotti
authors.forename: Wim
authors.initials: W
authors.lastname: De Borggraeve
authors.forename: Bernard
authors.initials: B
authors.lastname: Kaptein
authors.forename: Quirinus B
authors.initials: QB
authors.lastname: Broxterman
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Fernando
authors.initials: F
authors.lastname: Formaggio
authors.forename: Claudio
authors.initials: C
authors.lastname: Toniolo
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006909:Hydroxyproline / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; C456979:integramide A; D011392:Proline; D006909:Hydroxyproline