A Conformationally Restricted β-Strand HIV Protease Inhibitor

  • Michael C. Hillier
  • Stephen F. Martin
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)


The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel [-NH-Cα-] or [-CO-Cα-] bond replacements in pseudopeptides to restrict both side-chain orientation and enforce backbone secondary structures. To test these assumptions, the cyclopropane containing analog 1 (Fig. 1) was modeled after the potent HIV protease inhibitor 2, which together with a series of related derivatives was developed at Abbott Laboratories (11). This pseudopeptide contains a symmetrical diamino diol motif 8 (Fig. 2) flanked by Cbz-protected valine residues and is known to bind in a β-strand fashion at the enzyme-active site (12). Our analog 1 was designed to restrict the orientation of the valine residues and to mimic this “extended” backbone conformation. Comparison of enzyme inhibition constants for both compound 1 and the parent inhibitor 2 will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit.
Fig. 1.

HIV protease inhibitors.

Fig. 2.

Synthesis of the cyclopropane containing inhibitor 1.


Flash Chromatography Combine Organic Layer Backbone Conformation Carbodiimide Hydrochloride Pyridinium Chlorochromate 
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Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Michael C. Hillier
    • 1
  • Stephen F. Martin
    • 1
  1. 1.Department of ChemistryUniversity of Texas at AustinAustin

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