Die Wirksamkeit kleiner Tuberkulindosen gegen Lungenschwindsucht

Guttmann, Paul; Ehrlich, Paul H.

doi:10.1055/s-0029-1206570

Cited by 11 publications

(9 citation statements)

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“…[160,161] Methylene blue, which was used against malaria in the past, [195,196] is today the standard medication against methemoglobinemia and against ifosfamid-associated neurotoxicity. [178] Methylene blue has a number of desirable properties as an antimalarial drug.…”

Section: Drug Binding In the Central Cavitymentioning

confidence: 99%

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

2005

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Parasitic diseases such as sleeping sickness, Chagas' heart disease, and malaria are major health problems in poverty-stricken areas. Antiparasitic drugs that are not only active but also affordable and readily available are urgently required. One approach to finding new drugs and rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems in the pathogens. These antioxidant ensembles are essential to the parasites as they are attacked in the human host by strong oxidants such as peroxynitrite, hypochlorite, and H2O2. The pathogen-protecting system consists of some 20 thiol and dithiol proteins, which buffer the intraparasitic redox milieu at a potential of -250 mV. In trypanosomes and leishmania the network is centered around the unique dithiol trypanothione (N1,N8-bis(glutathionyl)spermidine). In contrast, malaria parasites have a more conservative dual antioxidative system based on glutathione and thioredoxin. Inhibitors of antioxidant enzymes such as trypanothione reductase are, indeed, parasiticidal but they can also delay or prevent resistance against a number of other antiparasitic drugs.

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Section: Drug Binding In the Central Cavitymentioning

confidence: 99%

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

2005

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“…Thus, most of the observed reaction describes the breakdown of the MDS. Methylene Blue in the Reductive and Oxidative Half-reaction-PfGR is the only verified enzymic target of the antimalarial dye methylene blue (13,19,20). The addition of 1-3 eq of inhibitor in the oxidative half-reaction did not affect the kinetic characteristics of the reaction.…”

Section: Spectralmentioning

confidence: 99%

Kinetic Characterization of Glutathione Reductase from the Malarial Parasite Plasmodium falciparum

Böhme¹,

Arscott²,

Becker³

et al. 2000

Journal of Biological Chemistry

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The homodimeric flavoenzyme glutathione reductase (GR) maintains high intracellular concentrations of the antioxidant glutathione (GSSG ؉ NADPH ؉ H ؉ 7 2 GSH ؉ NADP ؉ ). Due to its central function in cellular redox metabolism, inhibition of GR from the malarial parasite Plasmodium falciparum represents an important approach to antimalarial drug development; therefore, the catalytic mechanism of GR from P. falciparum has been analyzed and compared with the human host enzyme. The reductive half-reaction is similar to the analogous reaction with GR from other species. The oxidative halfreaction is biphasic, reflecting formation and breakdown of a mixed disulfide between the interchange thiol and GSH. The equilibrium between the E ox -EH 2 and GSSG-GSH couples has been modeled showing that the Michaelis complex, mixed disulfide-GSH, is the predominant enzyme form as the oxidative half-reaction progresses; rate constants used in modeling allow calculation of an K eq from the Haldane relationship, 0.075, very similar to the K eq of the same reaction for the yeast enzyme ( (S-S)⅐NADP؉ and E(FAD)(SH) 2 ⅐NADPH are dominant enzyme species in turnover. Since the individual forms of the enzyme differ in their susceptibility to inhibitors, the prevailing states of GR in the cell are of practical relevance.The glutathione disulfide/glutathione (GSSG/GSH) redox couple is present in most eukaryotic cells at millimolar concentrations (1). Major functions of GSH include the detoxification of reactive oxygen species by donation of reducing equivalents to glutathione peroxidase and glutathione S-transferase as well as enzyme regulation by thiol-disulfide interchange reactions (2). The flavoenzyme glutathione reductase (GR, 1 EC 1.6.4.2) catalyzes the reduction of GSSG to GSH and creates an intracellular GSH/GSSG ratio of 20 to 1000 depending on the respective metabolic conditions (3). Thus, glutathione reductase, a protein of 2 ϫ 55 kDa, plays a key role in cellular redox homeostasis. Both human GR (hGR) and Plasmodium falciparum GR (PfGR) are essential for the survival of the malarial parasite within the human erythrocyte (4, 5). The amino acid sequence identity between the two enzymes is 45% with two major features distinguishing them: (i) an insertion of 34 amino acids within the central domain (residues 318 -351) between the FAD binding motif and the highly conserved H8 helix (6); (ii) the differences in the amino acid residues lining the wall of the interface cavity, where only 8 out of 25 residues are conserved in PfGR. This cavity represents the binding site of many inhibitors including isoalloxazines, safranine, and menadione in human GR and could be the binding site of methylene blue in PfGR (7).Glutathione reductase belongs to the pyridine nucleotidedisulfide oxidoreductase family of homodimeric flavoenzymes that includes lipoamide dehydrogenase and thioredoxin reductase. Like other members of this family, each subunit of GR contains a disulfide and a flavin that are in redox contact. This ground state of the enzyme is ...

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“…50,51) Vennerstrom and co-workers reexamined the in vitro antimalarial potencies of xanthene, azine, oxazine, and thiazine dyes and reported that several of these dyes displayed strong in vitro activity against drug resistant P. falciparum. 47) In connection with our working DLC hypothesis, we examined the antimalarial potencies of several readily available dyes.…”

Section: )mentioning

confidence: 99%

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

Takasu

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, β-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.

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Die Wirksamkeit kleiner Tuberkulindosen gegen Lungenschwindsucht

Cited by 11 publications

References 0 publications

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

Kinetic Characterization of Glutathione Reductase from the Malarial Parasite Plasmodium falciparum

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

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