Design and synthesis of several small-size HTLV-I protease inhibitors with different hydrophilicity profiles

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2425-9. doi: 10.1016/j.bmcl.2011.02.066. Epub 2011 Feb 18.

Abstract

The human T cell leukemia/lymphotropic virus type 1 (HTLV-I) is clinically associated with adult T cell leukemia/lymphoma, HTLV-I associated myelopathy/tropical spastic paraparesis, and a number of other chronic inflammatory diseases. To stop the replication of the virus, we developed highly potent tetrapeptidic HTLV-I protease inhibitors. In a recent X-ray crystallography study, several of our inhibitors could not form co-crystal complexes with the protease due to their high hydrophobicity. In the current study, we designed, synthesized and evaluated the HTLV-I protease inhibition potency of compounds with hydrophilic end-capping moieties with the aim of improving pharmaceutic and pharmacokinetic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Computer-Aided Design
  • Crystallography, X-Ray
  • Drug Design
  • HIV Protease / chemistry
  • HIV Protease / metabolism
  • Human T-lymphotropic virus 1 / enzymology*
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / metabolism
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Peptides
  • Protease Inhibitors
  • Peptide Hydrolases
  • HIV Protease