Comparative Biochemistry and Drug Design for Infectious Disease

Cohen, Seymour S.

doi:10.1126/science.382357

Cited by 45 publications

(12 citation statements)

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“…In addition, they found that the activities of the enzymes f3-glycerophosphatase, ,B-N-acetylglucosaminidase, and,B-glucuronidase were decreased by 66%, 32%, and 20%, respectively, in Table 3. Effect of suramin on the activity of rat liver lysosomal enzymes in vitro (21), and is known to be teratogenic (22,23). Our results suggest that suramin binds to various lysosomal enzymes, including those involved in GAG degradation.…”

Section: Discussionmentioning

confidence: 69%

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Constantopoulos¹,

Rees²,

Cragg³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACGIntracerebral injection of the trypanocidal drug suramin in rats caused the formation of membranous neuronal and neuroglial inclusions. Here we show that intravenous administration of suramin, 500 mg/kg, to 2-month-old rats causes a 5-to 8-fold increase of glycosaminoglycan concentration in the liver within 10 days and a 6-fold increase in urinary glycosaminoglycan excretion. The excess glycosaminoglycans consist of heparan sulfate and dermatan sulfate. Intracerebral injection of 250 Ag of suramin results in a small increase of glycosaminoglycan and larger increase of ganglioside Gm2, GM3, and GD3 concentrations in the treated region of the brain. The activities of the lysosomal enzymes iduronate sulfatase, f-glucuronidase, and hyaluronidase in the liver of the suramintreated mature rats were consistently decreased, whereas those of a-L-iduronidase, heparan N-sulfatase, arylsulfatase B, and others were considerably increased. The activity of iduronate sulfatase was completely inhibited in vitro by suramin at concentrations of 50 pM or hi er. The activity of -glucuronidase was also strongly inhibited by low concentrations of suramin, but this inhibition was partially decreased at higher concentrations of the drug. The inhibition of both enzymes by suramin was noncom titive.-The suramin-treated rat may be a useful experimentaFanimal model of mucopolysaccharidosis.Mucopolysaccharidoses (MPS) are diseases caused by the heritable deficiency of lysosomal enzymes necessary for the degradation of glycosaminoglycans (GAG) (1, 2). The genetic defect results in tissue storage and excessive urinary excretion of various partially degraded GAG. In addition, most of these disorders are characterized by sphingolipid abnormalities, particularly of the brain (3). Recently, one of us found that intracerebral injection of the trypanocidal drug suramin resulted in the formation of membranous neuronal and neuroglial inclusions (4). It was suggested that these inclusion bodies may consist of glycolipids and GAG and that the experiment indicated a possible experimental model for storage diseases. The present study was conducted to examine biochemical alterations in the liver and in the brain of rats after intravenous and intracerebral injection of suramin. The pathologic changes found are similar to those detected in the genetic MPS (5) and suggest that the administration of suramin to rats may provide a useful model for the study of the pathogenesis of these diseases. A preliminary report of this work has been published(6). Table 1. Three groups of confrol rats received 0.5 ml of saline. Multiple intracerebral injections of suramin, totaling 40-250 ,ug in 10 ,l of saline (i.e., 4-25 ,ug/,ul) were given to 10-day-old and to 2-month-old rats. Control rats were given 10 ,l of saline. The rats were sacrificed between 7 and 10 days after injection. The livers were removed, weighed, and frozen in liquid nitrogen. Rats receiving intracerebral injections were sacrificed after 2-5 days. The regions of brain about 4 mm in diameter surr...

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Section: Discussionmentioning

confidence: 69%

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Constantopoulos¹,

Rees²,

Cragg³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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“…The general development of a rational approach to chemotherapy of parasites has been urged for some time (31)(32)(33). The success of the DFMO/bleomycin combination against a CNS model of T. brucei brucei represents the culmination of a progressive approach to chemotherapy of African trypanosomiasis.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of combinations of difluoromethylornithine and bleomycin in a mouse model of central nervous system African trypanosomiasis.

Clarkson¹,

Bacchi²,

Mellow³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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DL-ct-Difluoromethylornithine, a polyamine biosynthesis inhibitor, and bleomycin, a currently used antineoplastic agent, have each previously been shown to be curative for acute short-term infections of mice with Trypanosoma brucei brucei, an African trypanosome closely related to those that cause the human disease African sleeping sickness. These agents were tested singly and in combination in a previously described mouse model of sleeping sickness with demonstrable brain involvement. The original model is extended by using two additional strains of outbred mice and by demonstrating that melarsoprol, an arsenical and currently the only drug used for human African trypanosomiasis involving the brain, was also curative for these brain infections. Neither difluoromethylornithine nor bleomycin alone was curative for the brain infections; however, many combinations of the two drugs were found to be 100% curative with no evidence of immediate toxicity.Human African trypanosomiasis, or sleeping sickness, is caused by either of two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense. Although this tsetse flytransmitted disease has been controlled in many parts of Africa, outbreaks continue to occur. A recent example is the epidemic occurring in Uganda (1). Drugs available to treat this disease are generally quite toxic and not always curative; no new drugs have been introduced in the last 30 years. Melarsoprol, a toxic organic arsenical, is the only available drug that is effective in patients with advanced sleeping sickness-i.e., with central nervous system (CNS) involvement (2, 3).A major obstacle in the development of new drugs over the years has been the lack of a convenient and reliable laboratory model of the CNS infection. Recent studies of Jennings and colleagues (4)(5)(6) have demonstrated that a strain (TREU 667) of T. brucei brucei, a veterinary parasite, establishes CNS infections in mice and may thus provide a model of CNS trypanosomiasis. These semichronic infections are resistant to Berenil (diminazene aceturate), a widely used veterinary drug, if treatment is delayed for 3 weeks, even though such treatment ini-

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“…Proteins from parasitic organisms that are unique from analogous host proteins may serve as targets for chemotherapeutic agents [26]. In this regard, the protein kinase from the malarial parasite may be sufficiently different from host protein kinases that specific inhibitory drugs might be designed.…”

Section: Discussionmentioning

confidence: 99%

A plasmodium protein kinase that is developmentally regulated, stimulated by spermine, and inhibited by quercetin

Wiser

Eaton

Sheppard

1983

J of Cellular Biochemistry

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Plasmodium berghei-infected murine red cells possess protein kinase activity that is associated with the isolated parasites. Schizonts contain significantly higher levels of this protein kinase than the more immature forms, suggesting a relationship between this enzyme activity and parasite development. Partially purified protein kinase has a Km for ATP of approximately 30 microMs, whereas the Km for GTP is approximately 300 microMs and the substrate preference is phosvitin greater than casein much greater than histone greater than protamine. The Mg2+ optimum is 10-20 mM, and the protein kinase activity is stimulated by the polyamines spermine and spermidine. The flavone, quercetin, inhibits the protein kinase activity in a competitive manner with respect to ATP (Ki approximately 3 microMs), and P chabaudi also has a very similarly regulated protein kinase. Protein kinases from both species are very similar to the type I casein kinase.

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Comparative Biochemistry and Drug Design for Infectious Disease

Cited by 45 publications

References 45 publications

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Experimental animal model for mucopolysaccharidosis: suramin-induced glycosaminoglycan and sphingolipid accumulation in the rat.

Efficacy of combinations of difluoromethylornithine and bleomycin in a mouse model of central nervous system African trypanosomiasis.

A plasmodium protein kinase that is developmentally regulated, stimulated by spermine, and inhibited by quercetin

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