Publications by authors named "Ranae M Ranade"
Spontaneous Selection of Drug Resistance in a Calf Model of Infection.
Antimicrob Agents Chemother
May 2021
The intestinal protozoan is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA ( MetRS [MetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance.
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- Researchers developed two groups of new inhibitors for the enzyme methionyl-tRNA synthetase (MetRS) found in parasites, utilizing different chemical linkers in their design.
- Both groups of inhibitors were effective at low concentrations (EC < 10 nM) in stopping parasite growth, while showing minimal toxicity to human cells (CCs > 20,000 nM).
- Despite their effectiveness, the inhibitors had limited ability to cross the blood-brain barrier, indicating that further modifications are needed for treatment in advanced cases of human African trypanosomiasis.
Article Synopsis
- Methionyl-tRNA synthetase (MetRS) inhibitors are being researched for treating intestinal infections caused by the parasite Giardia lamblia, with Compound-1717 showing potential efficacy.
- Researchers developed a cell-based assay and a murine (mouse) model using engineered G. lamblia strains that express luciferase, allowing for effective quantification of the parasite in different life stages.
- The study demonstrated that Compound-1717 successfully cleared Giardia infection in mice within 3 days, indicating that MetRS inhibitors could be a promising avenue for developing new treatments for giardiasis.
Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Infection.
Antimicrob Agents Chemother
April 2019
Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating infections.
View Article and Find Full Text PDFBetter therapeutics are greatly needed to treat patients infected with trypanosomatid parasites such as or . This report describes 28 new imidazopyridines and triazolopyrimidines with potent and selective antitrypanosomal activity. Drug-like properties were demonstrated in a number of in vitro assays.
View Article and Find Full Text PDFMycobacterium tuberculosis is a pathogenic bacterial infectious agent that is responsible for approximately 1.5 million human deaths annually. Current treatment requires the long-term administration of multiple medicines with substantial side effects.
View Article and Find Full Text PDFDevelopment of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.
Antimicrob Agents Chemother
November 2017
Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm.
View Article and Find Full Text PDFA high throughput screening and subsequent hit validation identified compound as an inhibitor of parasite growth. Extensive structure-activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2-thiohydantoin () and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin (), with a EC of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound .
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- * Of these compounds, 7 and 12 showed effective in vitro activity against different parasites with an EC of ≤ 1 μM, and one compound was chosen for further testing due to its favorable properties.
- * In an acute mouse study, this selected compound showed promising results, inhibiting parasites similarly to the established treatment drug, benznidazole, indicating its potential as a new drug for treating trypanosomiasis.
Article Synopsis
- To enhance the effectiveness of these inhibitors, researchers investigated a binding fragment that targets a specific region known as the "enlarged methionine pocket" (EMP).
- This led to the discovery of a 6,8-dichloro-tetrahydroquinoline ring, which when substituted into compound 2 resulted in a new compound, 13, showing a remarkable potency with an EC of 4nM.
Article Synopsis
- The crystal structure of LdTyrRS (Leishmania donovani tyrosyl-tRNA synthetase) was determined at a resolution of 2.75 Å, revealing its complex with a nanobody and a tyrosyl adenylate analog.
- The nanobody stabilizes LdTyrRS by reducing the flexibility of a specific loop and allows for crucial interactions with the enzyme's active site, which is necessary for tRNA charging.
- An "extra pocket" (EP) near the adenine binding site presents a unique target for drug development to treat infections caused by L. donovani, potentially leading to therapies for various parasitic diseases due to similarities in other pathogenic protozoa.
Article Synopsis
- A screening of a compound library found a promising class of compounds, N-(2-aminoethyl)-N-phenyl benzamides, with potential against Trypanosoma brucei, the parasite causing Human African Trypanosomiasis.
- Researchers synthesized 82 analogues and discovered that compound 73 was particularly effective, showing a low effective concentration (EC) of 0.001μM in vitro tests.
- Compound 73 demonstrated good oral bioavailability and cured 2 out of 3 mice infected with the parasite when administered at a specific dosage, suggesting its potential use as a lead drug for treating the disease.
Article Synopsis
- Human African trypanosomiasis is a serious tropical disease that can be fatal without treatment, and current treatments have significant drawbacks like toxicity and limited effectiveness.
- A new compound, NEU-1053, has been discovered as a powerful and fast-acting treatment against the infection caused by Trypanosoma brucei in mouse models.
- Researchers are exploring variations of NEU-1053 to enhance its effectiveness and CNS exposure, and they are studying its effects and mechanisms through various methods, including X-ray crystallography.
Article Synopsis
- - The research builds on previous findings of 2-(2-benzamido)ethyl-4-phenylthiazole derivatives that showed potential against Trypanosoma brucei, which causes human African trypanosomiasis, but had poor metabolic stability.
- - This study focuses on synthesizing 65 new analogues through medicinal chemistry optimization, particularly targeting urea derivatives of 2-aryl-benzothiazol-5-amines for improved effectiveness.
- - One promising compound, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole, demonstrated high efficacy, achieving complete cures in mouse models for
Article Synopsis
- - A screening hit against Trypanosoma brucei methionyl-tRNA synthetase was enhanced using a structure-based method, leading to two new series of effective inhibitors: cyclic linker and linear linker series.
- - The compounds from both series showed strong inhibition of T. brucei growth with low toxicity to mammalian cells, particularly compound 16 and 31, which had effective concentrations of 39 nM and 22 nM, respectively.
- - Additionally, compound 31 demonstrated good pharmacokinetic properties after oral doses in mice and moderate brain permeability, making them promising candidates for developing new treatments for human African trypanosomiasis (HAT).
Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei.
View Article and Find Full Text PDFWe investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B.
View Article and Find Full Text PDFThe methionyl-tRNA synthetase (MetRS) is a novel drug target for the protozoan pathogen Giardia intestinalis. This protist contains a single MetRS that is distinct from the human cytoplasmic MetRS. A panel of MetRS inhibitors was tested against recombinant Giardia MetRS, Giardia trophozoites, and mammalian cell lines.
View Article and Find Full Text PDFA binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens.
Acta Crystallogr D Biol Crystallogr
August 2015
Article Synopsis
- Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that leads to severe health issues and currently has limited treatment options due to drug toxicity and poor effectiveness.
- Researchers focused on the structure of T. cruzi histidyl-tRNA synthetase (HisRS), a well-known drug target, to find specific inhibitors by screening small molecules that could bind to this protein.
- The study identified 15 fragments that bind to a crucial site on the HisRS protein, which could lead to the design of new, more effective drugs specifically targeting trypanosomatid HisRS for Chagas disease treatment.
Improved therapies for the treatment of Trypanosoma brucei, the etiological agent of the neglected tropical disease human African trypanosomiasis, are urgently needed. We targeted T. brucei methionyl-tRNA synthetase (MetRS), an aminoacyl-tRNA synthase (aaRS), which is considered an important drug target due to its role in protein synthesis, cell survival, and its significant differences in structure from its mammalian ortholog.
View Article and Find Full Text PDFAn estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease.
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- - TbMetRS is a crucial enzyme in Trypanosoma brucei that is being targeted for new antitrypanosomal drugs due to its essential role and adaptable structure when binding with various compounds.
- - A series of urea-based inhibitors (UBIs) have been developed that effectively inhibit TbMetRS with very low IC50 values and show the potential for oral use and crossing the blood-brain barrier, making them strong candidates for treating late-stage human African trypanosomiasis.
- - Structural analysis of 14 UBIs has revealed their binding interactions within TbMetRS, suggesting that they can fill key binding pockets without competing with ATP, pointing towards a novel drug design strategy that could be applied to other
Article Synopsis
- * From 110 analogues created, compound 64, a substituted 2-(3-aminophenyl)imidazopyridine, was found to have strong antiparasitic activity with an EC50 of just 2 nM and displayed favorable druglike characteristics in vitro.
- * This compound was effective when administered orally, curing infected mice at doses as low as 2.5 mg/kg, positioning compound 64 as a potential lead for new treatments against
New classes of antiparasitic drugs active against Trypanosoma brucei are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J.
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