Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases

Robert W. Miles, Peter C. Tyler, Gary B. Evans, Richard H. Furneaux, David W. Parkin, Vern L. Schramm

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Nucleoside N-ribohydrolases from protozoan parasites are targets for inhibitor design in these purine-auxotrophic organisms. Purine-specific and purine/pyrimidine-nonspecific nucleoside hydrolases have been reported. Iminoribitols that are 1-substituted with meta- and para-derivatized phenyl groups [(1S)-substituted 1,4-dideoxy-l,4-imino-D-ribitols] are powerful inhibitors for the nonspecific nucleoside N-ribohydrolases, but are weak inhibitiors for purine-specific isozymes [Parkin, D. W., Limberg, G., Tyler, P. C., Furneaux, R. H., Chen, X.-Y., and Schramm, V. L. (1997) Biochemisty 36, 3528-3534]. Binding of these inhibitors to nonspecific nucleoside hydrolase occurs primarily via interaction with the iminoribitol, a ribooxocarbenium ion analogue of the transition state. Weaker interactions arise from hydrophobic interactions between the phenyl group and the purine/pyrimidine site. In contrast, the purine-specific enzymes obtain equal catalytic potential from leaving group activation and ribooxocarbenium ion formation. Knowledge of the reaction mechanisms and transition states for these enzymes has guided the design of isozyme-specific transition state analogue inhibitors. New synthetic efforts have produced novel inhibitors that incorporate features of the leaving group hydrogen-bonding sites while retaining the iminoribitol group. These compounds provide the first transition state analogue inhibitors for purine-specific nucleoside hydrolase. The most inhibitory 1-substituted iminoribitol heterocycle is a sub-nanomolar inhibitor for the purine-specific nucleoside hydrolase from Trypanosoma brucei brucei. Novel nanomolar inhibitors are also described for the nonspecific nucleoside hydrolase from Crithidia fasciculata. The compounds reported here are the most powerful iminoribitol inhibitors yet described for the nucleoside hydrolases.

Original languageEnglish (US)
Pages (from-to)13147-13154
Number of pages8
JournalBiochemistry
Volume38
Issue number40
DOIs
StatePublished - Oct 5 1999

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N-Glycosyl Hydrolases
Isoenzymes
Crithidia fasciculata
Ribitol
Pyrimidine Nucleosides
Ions
Trypanosoma brucei brucei
Enzymes
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
purine
Parasites
Hydrogen bonds
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Miles, R. W., Tyler, P. C., Evans, G. B., Furneaux, R. H., Parkin, D. W., & Schramm, V. L. (1999). Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases. Biochemistry, 38(40), 13147-13154. https://doi.org/10.1021/bi990829u

Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases. / Miles, Robert W.; Tyler, Peter C.; Evans, Gary B.; Furneaux, Richard H.; Parkin, David W.; Schramm, Vern L.

In: Biochemistry, Vol. 38, No. 40, 05.10.1999, p. 13147-13154.

Research output: Contribution to journalArticle

Miles, RW, Tyler, PC, Evans, GB, Furneaux, RH, Parkin, DW & Schramm, VL 1999, 'Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases', Biochemistry, vol. 38, no. 40, pp. 13147-13154. https://doi.org/10.1021/bi990829u
Miles, Robert W. ; Tyler, Peter C. ; Evans, Gary B. ; Furneaux, Richard H. ; Parkin, David W. ; Schramm, Vern L. / Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases. In: Biochemistry. 1999 ; Vol. 38, No. 40. pp. 13147-13154.
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