Substrate-based inhibitors of HIV-1 protease

Summary

Peptide substrates of HIV-1 protease can be divided into two categories based on the nature of the scissile dipeptide and amino acid preference at the S2 and S2' subsites. Inhibitors based on substrate peptide sequences seem to fall into two similar categories as well. There has been tremendous progress in the design of inhibitors for the HIV protease since the first peptide-based inhibitors were described in 1989. Using a variety of different dipeptide isosteres, it has been possible to obtain highly potent, highly selective inhibitors of HIV protease which have Ki values in the subnanomolar range and which exhibit anti-infective activity in vitro in the nanomolar range. Protease inhibitors developed by Roche, Abbott, Searle and Dupont-Merck are currently undergoing clinical trials. The rapid progress in this field, the diversity of inhibitor types and the increasing use of structural information in designing nonpeptide inhibitors augurs well for future success of protease inhibitor-based therapy.

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Moore, M.L., Dreyer, G.B. Substrate-based inhibitors of HIV-1 protease. Perspectives in Drug Discovery and Design 1, 85–108 (1993). https://doi.org/10.1007/BF02171657

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Key words

  • HIV-1 protease
  • Substrates
  • Inhibitors
  • Structure-activity relationships