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S R Meshnick

Publications and source records attributed to S R Meshnick.

At least 55 records · Page 3Linked to original sources
PubMed1996

The mode of action of the antimalarial artemisinin and its derivatives.

1. Atremisinin (qinghaosu) is a sesquiterpene endoperoxide derived from a plant which was used in Chinese herbal medicine for thousands of years. 2. Artemisinin and its derivatives have potent antimalarial activity, and are now being used clinically in much of the world. 3. The artemisinin derivatives have an unusual mode of action involving the iron-catalyzed generation of a carbon-centered free radical followed by the alkylation of malaria-specific proteins.

Animals↗
PubMed1996

Patterns of haemozoin accumulation in tissue.

A sensitive fluorometric method for assaying malarial pigment, haemozoin, has been developed and used to determine the haemozoin content of blood and tissue samples. Plasmodium falciparum rings and trophozoites were found to contain 23 and 339 ng haemozoin/10(6) parasitized red blood cells (PRBCs), respectively. Unsynchronized Plasmodium berghei NK65 or ANKA parasites from infected mice contained 27 and 61 ng haemozoin/10(6) PRBCs, respectively. An exponential accumulation of haemozoin within 18 days after infection was demonstrated in liver and spleen tissue, representing up to 0.2% of the tissue by wet weight by day 18. Histology indicated that the accumulation occurred predominantly in the tissue monocytes. In the brain, the levels of haemozoin after 8 days of infection were considerably lower than they were in the liver or spleen, and most of the pigment appeared to be that present inside parasitized red blood cells. CBA/Ca mice infected with P. berghei ANKA (a cerebral malaria model) had significantly higher amounts of haemozoin in the brain than did ICR mice infected with P. berghei NK65. Thus, haemozoin levels in tissue increase with the duration of infection, and its presence may be associated with cerebral pathology.

Anemia↗
PubMed1996

Is haemozoin a target for antimalarial drugs?

Malarial parasites utilize a unique pathway to degrade haemoglobin. Most of the haem which is released during haemoglobin degradation is incorporated into haemozoin. The mechanism of haemozoin synthesis and the structure of haemozoin are controversial. Neither chloroquine nor artemisinin appear to affect haemozoin synthesis in vivo. Artemisinin is activated by intraparasitic haem and iron into a free radical which then alkylates specific malarial proteins.

Animals↗
PubMed1996

Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy.

Artemisinin and its derivatives are endoperoxide-containing compounds which represent a promising new class of antimalarial drugs. In the presence of intraparasitic iron, these drugs are converted into free radicals and other electrophilic intermediates which then alkylate specific malaria target proteins. Combinations of available derivatives and other antimalarial agents show promise both as first-line agents and in the treatment of severe disease.

Animals↗
PubMed1995

Syntheses and antimalarial activities of N-substituted 11-azaartemisinins.

A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

Animals↗
PubMed1995

Pteroylpolyglutamate synthesis by lung- and culture-derived Pneumocystis carinii.

Pneumocystis carinii synthesizes folates de novo from exogenous p-aminobenzoic acid (pABA). Lung-derived organisms take up [3H]pABA in vitro except in the presence of sulfamethoxazole. Supernatants from spinner-flask cultures take up [3H]pABA if they were inoculated with lungs from infected rats, but not if they were inoculated with lungs from uninfected rats. P. carinii folates consist primarily of pteroylpentaglutamates. Plasmodium falciparum, in contrast, contains primarily pteroyltetraglutamates. Culture-derived organisms synthesize folates at a four-fold higher specific activity than lung-derived organisms, possibly because they contain less contaminating lung debris. These data suggest that P. carinii remains metabolically active in culture for at least 4 days.

4-Aminobenzoic Acid↗
PubMed1995

Synthesis and antimalarial activities of several fluorinated artemisinin derivatives.

The carbonyl groups in several artemisinin derivatives were converted into geminal difluorinated compounds on treatment with diethylaminosulfur trifluoride. A number of other mono- and polyfluorinated artemisinin derivatives were prepared. Their in vitro antimalarial activities were all equal to or greater than the nonfluorinated analogs or precursors.

Animals↗
PubMed1995

Structure-activity relationships of lactone ring-opened analogs of the antimalarial 1,2,4-trioxane artemisinin.

1,2,4-Trioxane benzylic ethers 8a-e were prepared as simplified, tricyclic versions of the clinically used tetracyclic antimalarial drug artemisinin (1). Five additional artemisinin analogs (9-11) were prepared. Neither water solubility (analogs 8e and 11b) nor chelating ability (analogs 9 and 10), however, produced trioxanes of especially high in vitro antimalarial activity. Trioxane fluorobenzyl ether 8b is the most active in this series (more active than artemisinin) against Plasmodium falciparum parasites in vitro, with substantial activity also in mice infected with Plasmodium berghei parasites and with 10 times higher activity than artemisinin (1) in killing immature P. falciparum gametocytes.

Animals↗
PubMed1995

Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: docking between the antimalarial agent and its putative receptor.

Artemisinin (qinghaosu, QHS) is a promising new antimalarial agent that is effective against drug-resistant strains of malaria. The antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.

Antimalarials↗
PubMed1995

Methionine recycling pathways and antimalarial drug design.

5'-Deoxy-5'-(methylthio)adenosine (MTA) is an S-adenosylmethionine metabolite that is generated as a by-product of polyamine biosynthesis. In mammalian cells, MTA undergoes a phosphorolytic cleavage catalyzed by MTA phosphorylase to produce adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTRP). Adenine is utilized in purine salvage pathways, and MTRP is subsequently recycled to methionine. Whereas some microorganisms metabolize MTA to MTRP via MTA phosphorylase, others metabolize MTA to MTRP in two steps via initial cleavage by MTA nucleosidase to adenine and 5-deoxy-5-(methylthio)ribose (MTR) followed by conversion of MTR to MTRP by MTR kinase. In order to assess the extent to which these pathways may be operative in Plasmodium falciparum, we have examined a series of 5'-alkyl-substituted analogs of MTA and the related MTR analogs and compared their abilities to inhibit in vitro growth of this malarial parasite. The MTR analogs 5-deoxy-5-(ethylthio)ribose and 5-deoxy-5-(hydroxyethylthio)ribose were inactive at concentrations up to 1 mM, and 5-deoxy-5-(monofluoroethylthio)ribose was weakly active (50% inhibitory concentration = 700 microM). In comparison, the MTA analogs, 5'-deoxy-5'-(ethylthio)adenosine,5'-deoxy-5'-(hydroxyethylthio)ade nosine (HETA), and 5'-deoxy-5'-(monofluoroethylthio)adenosine, had 50% inhibitory concentrations of 80, 46, and 61 microM, respectively. Extracts of P. falciparum were found to have substantial MTA phosphorylase activity. Coadministration of MTA with HETA partially protected the parasites against the growth-inhibitory effects of HETA. Results of this study indicate that P. falciparum has an active MTA phosphorylase that can be targeted by analogs of MTA.

Animals↗
PubMed1995

Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase.

Dihydroorotate dehydrogenase (DHOD) is a pyrimidine biosynthetic enzyme which is usually directly linked to the mitochondrial respiratory chain. Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport. Since atovaquone also has therapeutic activity against Pneumocystis carinii, the P. carinii DHOD may also be an important drug target. Organisms were obtained from immunosuppressed rats, incubated for 24 h in a short-term in vitro culture system, and then lysed. P. carinii lysates catalyzed the generation of orotate from dihydroorotate at a rate of 852 pmol/mg of protein per min. Control preparations made from uninfected mice showed much less total enzymatic activity and enzyme specific activity. As expected, P. carinii DHOD activity was susceptible to respiratory inhibitors such as cyanide, antimycin A, and salicylhydroxamic acid (SHAM). Susceptibility to SHAM suggests the presence of an alternative oxidase. In contrast, neither pentamidine nor 5-hydroxy-6-demethylprimaquine (5H6DP), a quinone metabolite of primaquine, inhibited the enzyme. Atovaquone inhibited DHOD by 76.3% at 100 microM and 36.5% at 10 microM. A similar degree of inhibition was found when the organisms were preincubated with the drug. Atovaquone inhibited P. carinii growth in vitro at a somewhat lower concentration (between 0.3 and 3 microM). In contrast, Plasmodium falciparum growth and enzyme activity are susceptible to nanomolar concentrations of atovaquone. Thus, while it is possible that atovaquone acts by inhibiting the P. carinii electron transport chain, the possibility of another drug target cannot be excluded.

Animals↗
PubMed1995

Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs.

Forty-four sulfa drugs were screened against crude preparations of recombinant Pneumocystis carinii dihydropteroate synthetase. The apparent Michaelis-Menten constants (Km) for p-aminobenzoic acid and 7,8-dihydro-6-hydroxymethylpterin pyrophosphate were 0.34 +/- 0.02 and 2.50 +/- 0.71 microM, respectively. Several sulfa drugs, including sulfathiazole, sulfachlorpyridazine, sulfamethoxypyridazine, and sulfathiourea, inhibited dihydropteroate synthetase approximately as well as sulfamethoxazole, as determined by the concentrations which cause 50% inhibition and/or by Ki. For all sulfones and sulfonamides tested, unsubstituted p-amino groups were necessary for activity, and sulfonamides containing an N1-heterocyclic substituent were found to be the most effective inhibitors. Folate biosynthesis in isolated intact P. carinii was approximately equally sensitive to inhibition by sulfamethoxazole, sulfachlorpyridazine, sulfamethoxypyridazine, sulfisoxazole, and sulfathiazole. Two of these drugs, sulfamethoxypyridazine and sulfisoxazole, are known to be less toxic than sulfamethoxazole and should be further evaluated for the treatment of P. carinii pneumonia.

Animals↗
PubMed1994

Alkylation of proteins by artemisinin. Effects of heme, pH, and drug structure.

Artemisinin and its derivatives are a promising new class of antimalarial agents containing an endoperoxide bridge. [14C]Artemisinin alkylated various proteins in vitro. Between 5 and 18% of added drug bound to hemoproteins such as catalase, cytochrome c, and hemoglobin. However, it did not react with heme-free globin. For catalase and hemoglobin, most of the drug reacted with the protein moiety rather than the heme. Artemisinin bound to human serum albumin (HSA) more efficiently at pH 8.6 than 7.4, more efficiently in Dulbecco's PBS than in Tris-HCl buffer, and better when HSA had been made fatty acid-free. Dihydroartemisinin also bound to HSA, whereas deoxyartemisinin, an inactive derivative, did not. There was no binding between DNA and artemisinin. These data provide insight into the mechanism of the reaction between artemisinin and proteins.

Alkylating Agents↗
PubMed1994

Auxotrophs of Plasmodium falciparum dependent on p-aminobenzoic acid for growth.

The isolation of auxotrophic strains of a parasite offers new opportunities for studying parasitology. We have isolated cloned lines of Plasmodium falciparum that, unlike the parent line from which they were derived, rely on exogenous p-aminobenzoic acid (PABA) for growth. Isolation involved random mutagenesis of a cloned line of P. falciparum and subsequent selection of PABA-dependent parasites. Both parent and PABA-dependent clones were analyzed for PABA uptake and synthesis. Each clone takes up comparable amounts of PABA from the medium. The parent line, clone 3D7, can synthesize PABA de novo, whereas the PABA-dependent clones cannot. The requirement of exogenous PABA for growth by the auxotrophic strains coupled with their inability to synthesize PABA indicates that normal parasite growth can be completely supported by either synthesis or salvage. This work further clarifies the relationship between the availability of PABA and success of the parasite, an issue of debate from classic studies showing reduced parasite load in individuals on milk-fed diets.

4-Aminobenzoic Acid↗
PubMed1994

The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase.

Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimidine biosynthesis and the major source of electrons for the mitochondrial electron transport chain of intraerythrocytic malaria parasites. DHOD and the electron transport chain may also be the site of inhibition by certain antimalarial drugs. In order to test this, Plasmodium falciparum-infected erythrocytes were exposed in vitro to artemisinin or various 8-aminoquinolines, such as primaquine, WR 238605, WR 225448, and WR 255956, and then assayed for both enzyme activity and [3H]hypoxanthine incorporation, which is an indicator of viability. Atovaquone inhibits DHOD activity to a much greater extent than hypoxanthine incorporation, which is consistent with previous reports that it targets the parasite respiratory chain. However, artemisinin and the 8-aminoquinolines inhibit DHOD to the same or lesser extent than hypoxanthine incorporation, suggesting that these compounds have different modes of action.

Animals↗