Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'-groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex

Bioorg Med Chem. 2003 Mar 20;11(6):1107-15. doi: 10.1016/s0968-0896(02)00535-7.

Abstract

A series of HIV-1 protease inhibitors having new tetrahydrofuran P2/P2' groups have been synthesised and tested for protease inhibition and antiviral activity. Six novel 4-aminotetrahydrofuran derivatives were prepared starting from commercially available isopropylidene-alpha-D-xylofuranose yielding six symmetrical and six unsymmetrical inhibitors. Promising sub nanomolar HIV-1 protease inhibitory activities were obtained. The X-ray crystal structure of the most potent inhibitor (23, K(i) 0.25 nM) co-crystallised with HIV-1 protease is discussed and the binding compared with inhibitors 1a and 1b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Drug Design
  • Furans / chemistry*
  • HIV Protease / chemistry*
  • HIV Protease / drug effects
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / enzymology*
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation

Substances

  • Furans
  • HIV Protease Inhibitors
  • Indicators and Reagents
  • HIV Protease