Protein structure-based design of anti-protozoal drugs

Verlinde, Christophe L. M. J.; Bressi, Jerome C.; Choe, Juhui; Suresh, Stephen; Buckner, Frederick S.; Voorhis, Wesley C. Van; Michels, Paul A.M.; Gelb, Michael H.; Hól, Wim G. J.

doi:10.1590/s0103-50532002000600018

Cited by 9 publications

(5 citation statements)

References 17 publications

(18 reference statements)

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“…A number of approaches will be taken to identify additional GAPDHS inhibitors, including substructure searches to identify similar compounds from our in house library and external libraries, and using structure-based drug design which has already proved successful for targeting GAPDH in parasites [ 15 , 18 - 20 ]. Structures for human GAPDHS are available in the pdb database (3PFW and 3H9E) and will be used for assessing both our current hits and for structure-based drug design approaches.…”

Section: Discussionmentioning

confidence: 99%

“…Compounds to inhibit pro-apoptotic activity of human GAPDH are also being investigated [ 14 ]. GAPDH has also proven to be an attractive drug target in protozoa [ 15 ] such as trypanosomes [ 16 ] and Entamoeba [ 17 ], since many of these parasites rely solely on glycolysis for their energy supply. Structure- and catalytic mechanism-based approaches have been applied to design compounds that inhibit the glycolytic enzymes of the parasites without affecting the corresponding proteins of the human host [ 18 - 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS)

Sexton¹,

Danshina

Lamson³

et al. 2011

Curr Chem Genomics

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Glycolytic isozymes that are restricted to the male germline are potential targets for the development of reversible, non-hormonal male contraceptives. GAPDHS, the sperm-specific isoform of glyceraldehyde-3-phosphate dehydrogenase, is an essential enzyme for glycolysis making it an attractive target for rational drug design. Toward this goal, we have optimized and validated a high-throughput spectrophotometric assay for GAPDHS in 384-well format. The assay was stable over time and tolerant to DMSO. Whole plate validation experiments yielded Z’ values >0.8 indicating a robust assay for HTS. Two compounds were identified and confirmed from a test screen of the Prestwick collection. This assay was used to screen a diverse chemical library and identified fourteen small molecules that modulated the activity of recombinant purified GAPDHS with confirmed IC50 values ranging from 1.8 to 42 µM. These compounds may provide useful scaffolds as molecular tools to probe the role of GAPDHS in sperm motility and long term to develop potent and selective GAPDHS inhibitors leading to novel contraceptive agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS)

Sexton¹,

Danshina

Lamson³

et al. 2011

Curr Chem Genomics

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“…Parasitic diseases have an overwhelming impact on public health, and their geographical distribution favors climates that allow vector persistence for transmission. Vector control is possible, eradication is probably not possible, and vaccine development has so far been unsuccessful, as parasites are experts at evading or deregulating the human immune system [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Microorganisms as a Potential Source of Molecules to Control Trypanosomatid Diseases

et al. 2021

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Trypanosomatids are the causative agents of leishmaniasis and trypanosomiasis, which affect about 20 million people in the world’s poorest countries, leading to 95,000 deaths per year. They are often associated with malnutrition, weak immune systems, low quality housing, and population migration. They are generally recognized as neglected tropical diseases. New drugs against these parasitic protozoa are urgently needed to counteract drug resistance, toxicity, and the high cost of commercially available drugs. Microbial bioprospecting for new molecules may play a crucial role in developing a new generation of antiparasitic drugs. This article reviews the current state of the available literature on chemically defined metabolites of microbial origin that have demonstrated antitrypanosomatidactivity. In this review, bacterial and fungal metabolites are presented; they originate from a range of microorganisms, including cyanobacteria, heterotrophic bacteria, and filamentous fungi. We hope to provide a useful overview for future research to identify hits that may become the lead compounds needed to accelerate the discovery of new drugs against trypanosomatids.

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“…The repertoire of drugs to fight protozoa diseases such as Malaria, Chagas disease, Leishmaniasis and African trypanomiasis is woefully inadequate (Verlinde et al, 2002;Chatelain and Ioset, 2001;Gonzalez and Cerecetto, 2011). Since it is unlikely that any new and less toxic drug will be developed for this disease in the near future, increasing attention is now being focused on the potential of existing compounds, either alone or in combination chemotherapy for improved efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

Comparative efficacy of Berenil and Samorin in albino rats experimentally infected with current field isolates of <i>Trypanosoma brucei brucei</i>

Oo¹,

Toshak²,

Obaloto³

et al. 2014

Int. J. Bio. Chem. Sci

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The efficacy of two standard veterinary trypanocides, diminazene aceturate (Berenil-therapeutic) and isometamidium chloride (Samorin-prophylactic) was compared in albino rats experimentally infected with current field isolate of Trypanosoma brucei brucei (Federe strain). The study consisted of forty albino rats, divided into 8 groups of five animals each. The negative control was uninfected and untreated (Group 1), whereas the positive control was infected and untreated (Group 2). Other groups were treated intramuscularly with either 0.5 mg/kg or 3.5 mg/kg body weight of Samorin or Berenil respectively adopting different protocols. Groups 3 and 4 were treated the same day of infection with Berenil and Samorin respectively (treatment was before infection). Groups 5 and 6 were treated at patency (4 days post infection) with Berenil and Samorin respectively. Groups 7 and 8 were infected before treatment on the same day with Berenil and Samorin respectively, and re-challenged with the T.brucei brucei after four days. The results obtained 60 days post treatment showed that the difference between the efficacies of the two drugs was significant (P< 0.05). Berenil cleared the parasites more from the blood of the albino rats than Samorin. From the recorded values of the parameters (body weight, temperature, packed cell volume and parasitaemic profile), it was concluded that Berenil is a more efficacious trypanocide than Samorin, and is recommended as the drug of choice in the treatment of animal trypanosomiasis.

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Protein structure-based design of anti-protozoal drugs

Cited by 9 publications

References 17 publications

Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS)

Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS)

Microorganisms as a Potential Source of Molecules to Control Trypanosomatid Diseases

Comparative efficacy of Berenil and Samorin in albino rats experimentally infected with current field isolates of <i>Trypanosoma brucei brucei</i>

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