Inhibition of HIV-1 Pretense by Novel Dipeptide Isosteres Containing 2-Isoxazoline or $\alpha$-Hydroxy Ketomethylene

  • Kim, Do-Hyung (Department of Life Science and Center for Biofunctional Mocelules) ;
  • Park, Kwan-Yong (Department of Life Science and Center for Biofunctional Mocelules) ;
  • Chung, Yong-Jun (Department of Chemistry Pohang University of Science and Technology Pohang) ;
  • Kim, Byeang-Hyean (Department of Chemistry Pohang University of Science and Technology Pohang)
  • Published : 1994.08.01

Abstract

Human immunodeficiency virus type 1 (HIV-1) protease is essential for the replication of the virus and it is therefore an attractive target for antiviral drugs of HIV-1. Several dipeptide isosteres containing 2-isoxazoline or $\alpha$-hydroxy ketomethylene have been synthesized and their inhibitory effects on the HIV-1 protease examined. The enzymatically active HIV-1 protease was purified to homogeniety from E. coli transformed with a recombinant plasmid (pMAL-pro) containing the entire gene encoding the protease. The purified protease had the substrate specificity with Km value of 9.8$\mu$M when an undecapeptide His-Lys-Ala-Arg-Val-Leu-(p-nitro)Phe-Glu-Ala-Nle-Ser-amide was used as a substrate, and the products from the substrate after specific cleavage by HIV-1 protease were analyzed by HPLC. The synthetic compounds containing dipeptide isosteres showed specific inhibitory effects while a dipeptide isostere containing an isoxazoline ring inhibited the HIV-1 protease competitively with Ki value of 500 $\mu$M. Even if the inhibition effects of HIV-1 protease were not very high, these novel dipeptide isosteres can be used as key structural moieties for developing specific inhibitors of HIV-1 protease.

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