Synthesis of 5′-methylthio coformycins: Specific inhibitors for malarial adenosine deaminase

Peter C. Tyler, Erika A. Taylor, Richard F G Fröhlich, Vern L. Schramm

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Transition state theory suggests that enzymatic rate acceleration (k cat/knon) is related to the stabilization of the transition state for a given reaction. Chemically stable analogues of a transition state complex are predicted to convert catalytic energy into binding energy. Because transition state stabilization is a function of catalytic efficiency, differences in substrate specificity can be exploited in the design of tight-binding transition state analogue inhibitors. Coformycin and 2′-deoxycoformycin are natural product transition state analogue inhibitors of adenosine deaminases (ADAs). These compounds mimic the tetrahedral geometry of the ADA transition state and bind with picomolar dissociation constants to enzymes from bovine, human, and protozoan sources. The purine salvage pathway in malaria parasites is unique in that Plasmodium falciparum ADA (PfADA) catalyzes the deamination of both adenosine and 5′-3 methylthioadenosine. In contrast, neither human adenosine deaminase (HsADA) nor the bovine enzyme (BtADA) can deaminate 5′-methylthioadenosine. 5′-Methylthiocoformycin and 5′-methylthio-2′-deoxycoformycin were synthesized to be specific transition state mimics of the P. falciparum enzyme. These analogues inhibited PfADA with dissociation constants of 430 and 790 pM, respectively. Remarkably, they gave no detectable inhibition of the human and bovine enzymes. Adenosine deamination is involved in the essential pathway of purine salvage in P. falciparum, and prior studies have shown that inhibition of purine salvage results in parasite death. Inhibitors of HsADA are known to be toxic to humans, and the availability of parasite-specific ADA inhibitors may prevent this side-effect. The potent and P. falciparum-specti'ic inhibitors described here have potential for development as antimalarials without inhibition of host ADA.

Original languageEnglish (US)
Pages (from-to)6872-6879
Number of pages8
JournalJournal of the American Chemical Society
Volume129
Issue number21
DOIs
StatePublished - May 30 2007

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Coformycin
Adenosine Deaminase Inhibitors
Adenosine Deaminase
Plasmodium falciparum
Salvaging
Enzymes
Pentostatin
Deamination
Parasites
Adenosine
Stabilization
Enzyme inhibition
Poisons
Antimalarials
Biological Products
Binding energy
Substrate Specificity
Malaria
Availability
Cats

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Synthesis of 5′-methylthio coformycins : Specific inhibitors for malarial adenosine deaminase. / Tyler, Peter C.; Taylor, Erika A.; Fröhlich, Richard F G; Schramm, Vern L.

In: Journal of the American Chemical Society, Vol. 129, No. 21, 30.05.2007, p. 6872-6879.

Research output: Contribution to journalArticle

Tyler, Peter C. ; Taylor, Erika A. ; Fröhlich, Richard F G ; Schramm, Vern L. / Synthesis of 5′-methylthio coformycins : Specific inhibitors for malarial adenosine deaminase. In: Journal of the American Chemical Society. 2007 ; Vol. 129, No. 21. pp. 6872-6879.
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