Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors

Karl A. Scheidt, William R. Roush*, James H. McKerrow, Paul M. Selzer, Elizabeth Hansell, Philip J. Rosenthal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


The inhibition of cysteine proteases is being studied as a strategy to combat parasitic diseases such as Chagas' disease, leishmaniasis, and malaria. Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiologic agent of Chagas' disease. A crystal structure of cruzain, covalently inactivated by fluoromethyl ketone inhibitor 1 (Cbz-Phe-Ala-FMK), was used as a template to design potential inhibitors. Conformationally constrained γ-lactams containing electrophilic aldehyde (12, 17, 18, 25, 26, and 29) or vinyl sulfone (43, 44, and 46) units were synthesized. Constrained lactam 26 had IC50 values of ca. 20nM against the Leishmania major protease and ca. 50nM versus falcipain, an important cysteine protease isolated from Plasmodium falciparum. However, all of the conformationally constrained inhibitors were weak inhibitors of cruzain, compared to unconstrained peptide aldehyde (e.g. 5 ) and vinyl sulfone inhibitors (e.g. 48, which proved to be an excellent inhibitor of cruzain with an apparent second order inhibition rate constant (k(inact)/K(i)) of 634,000s-1M-1). A significant reduction in activity was also observed with acyclic inhibitors 30 and 51 containing α-methyl phenylalanine residues at the P2 position. These data indicate that the pyrrolidinone ring, especially the quarternary center at P2, interferes with the normal substrate binding mode with cruzain, but not with falcipain or the leishmania protease. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2477-2494
Number of pages18
JournalBioorganic and Medicinal Chemistry
Issue number12
StatePublished - Dec 1998


  • Conformationally constrained peptidyl aldehydes
  • Cysteine protease inhibitors
  • Peptidyl vinyl sulfones

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry


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