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. 2010 Sep 15;18(18):6771-5.
doi: 10.1016/j.bmc.2010.07.050. Epub 2010 Jul 25.

Peptidic HIV integrase inhibitors derived from HIV gene products: structure-activity relationship studies

Shintaro Suzuki  1 , Kasthuraiah Maddali, Chie Hashimoto, Emiko Urano, Nami Ohashi, Tomohiro Tanaka, Taro Ozaki, Hiroshi Arai, Hiroshi Tsutsumi, Tetsuo Narumi, Wataru Nomura, Naoki Yamamoto, Yves Pommier, Jun A Komano, Hirokazu Tamamura
Affiliations

Peptidic HIV integrase inhibitors derived from HIV gene products: structure-activity relationship studies

Shintaro Suzuki et al. Bioorg Med Chem. .

Abstract

Structure-activity relationship studies were conducted on HIV integrase (IN) inhibitory peptides which were found by the screening of an overlapping peptide library derived from HIV-1 gene products. Since these peptides located in the second helix of Vpr are considered to have an alpha-helical conformation, Glu-Lys pairs were introduced into the i and i+4 positions to increase the helicity of the lead compound possessing an octa-arginyl group. Ala-scan was also performed on the lead compound for the identification of the amino acid residues responsible for the inhibitory activity. The results indicated the importance of an alpha-helical structure for the expression of inhibitory activity, and presented a binding model of integrase and the lead compound.

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Figures

Figure 1
Figure 1
Amino acid sequences of compounds 1–5. Compounds 1–3 are consecutive overlapping peptides with free N-/C-terminus. These were found by the IN inhibitory screening of a peptide library derived from HIV-1 gene products. Compounds 4 and 5 are cell penetrative leads of IN inhibitors.
Figure 2
Figure 2
Amino acid sequences of compounds 6–10, which are elongated by one amino acid from compound 4 to 5.
Figure 3
Figure 3
Amino acid sequences of compounds 11–17, into which Glu-Lys pairs have been introduced.
Figure 4
Figure 4
Luciferase signals in MT-4 Luc cells infected with HIV-1 in the presence of different concentrations of compounds 11–17. Luciferase activity is expressed as relative luciferase units (RLU). 3TC is an HIV reverse transcriptase inhibitor, which was used as a positive control.
Figure 5
Figure 5
CD spectra of compounds 5 and 11–17 (5 µM) in 0.1 M phosphate buffer, pH 5.6 containing 50% MeOH at 25 °C.
Figure 6
Figure 6
Amino acid sequences of compounds 18–29 based on an Ala-scan of compound 4. Position numbers correspond to alignment with compound 5.
Figure 7
Figure 7
Luciferase signals in MT-4 Luc cells infected with HIV-1 in the presence of various concentrations of compounds 18–29. Luciferase activity was valued as RLU.
Figure 8
Figure 8
Brief presumed drawing of the binding model of HIV-1 IN and compound 5.
See this image and copyright information in PMC

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