Fragment‐Based Phenotypic Lead Discovery: Cell‐Based Assay to Target Leishmaniasis

Ayotte, Yann; Bilodeau, François; Descoteaux, Albert; LaPlante, Steven R.

doi:10.1002/cmdc.201800161

Cited by 13 publications

(17 citation statements)

References 63 publications

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“…Approximately 2500 compounds, mostly from a well-curated library of fragment compounds (18), were screened to identify candidates with the ability to completely inhibit the growth of N. meningitidis at 100 μM after 16 h at 37°C. As presented in Figure 1A, showing a sample of these results, only 17 compounds (approximately 0,7% of the library) met this criterion.…”

Section: Downloaded Frommentioning

confidence: 99%

Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

Bernet

Lebughe

Vincent

et al. 2021

Antimicrob Agents Chemother

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Neisseria meningitidis and Neisseria gonorrhoeae, two highly related species that may have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection, whereas for N. gonorrhoeae, there are only a limited number of antibiotics available. Unfortunately, some strains of these species are rapidly evolving and capable of escaping human interventions. Thus, it is now urgent to develop new avenues to fight these bacteria. This study reports that a boron-based salt, sodium tetraphenylborate (NaBPh4), displays high bactericidal activity and remarkable specificity against N. meningitidis and N. gonorrhoeae. Other closely related commensal species such as N. lactamica, found in the normal flora of healthy individuals were found to be less affected even at 5-fold higher doses of NaBPh4. This specificity was further observed where much lower sensitivity was found for the more distant Neisseriaceae (such as N. elongata or Kingella oralis) and completely unrelated species. A significant boron uptake by N. meningitidis cells was observed after incubation with 5 μM of NaBPh4, as measured by ICP-MS, suggesting that this drug candidate's target(s) could be located intracellularly or within the cell envelope. Furthermore, mutants with a slightly decreased susceptibility displayed an alteration in genes coding for cell-envelope elements, which reduced their virulence in an animal model of infection. Finally, a single dose of NaBPh4 resulted in a significant reduction in bacterial burden in a mouse model of N. meningitidis bacteremia. Although numerous boron-containing species were previously reported for their complex biological activities, the observation of this narrow selectivity is unprecedented and of potential importance from a therapeutic standpoint.

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Section: Downloaded Frommentioning

confidence: 99%

Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

Bernet

Lebughe

Vincent

et al. 2021

Antimicrob Agents Chemother

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“…A recent review provides an excellent overview of these and other small-molecule discovery technologies with examples (Markossian et al 2018 ), and comparative analyses have been carried out as well (Riddy et al 2018 ). A search of the literature yields a plethora of phenotypic drug discovery approaches, developments, and applications (e.g., Ayotte et al 2018 ; Chatelain and Ioset 2018 ; Lagunin et al 2018 ; Lane et al 2018 ; Orellana et al 2018 ; Ortiz et al 2017 ), and finally, a cautionary note was also put forward (Copeland and Boriack-Sjodin 2018 ).…”

Section: Phenotypic Drug Discoverymentioning

confidence: 99%

Precision medicine review: rare driver mutations and their biophysical classification

et al. 2019

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How can biophysical principles help precision medicine identify rare driver mutations? A major tenet of pragmatic approaches to precision oncology and pharmacology is that driver mutations are very frequent. However, frequency is a statistical attribute, not a mechanistic one. Rare mutations can also act through the same mechanism, and as we discuss below, Blatent driver^mutations may also follow the same route, with Bhelper^mutations. Here, we review how biophysics provides mechanistic guidelines that extend precision medicine. We outline principles and strategies, especially focusing on mutations that drive cancer. Biophysics has contributed profoundly to deciphering biological processes. However, driven by data science, precision medicine has skirted some of its major tenets. Data science embodies genomics, tissue-and cell-specific expression levels, making it capable of defining genome-and systems-wide molecular disease signatures. It classifies cancer driver genes/mutations and affected pathways, and its associated protein structural data guide drug discovery. Biophysics complements data science. It considers structures and their heterogeneous ensembles, explains how mutational variants can signal through distinct pathways, and how allo-network drugs can be harnessed. Biophysics clarifies how one mutation-frequent or rare-can affect multiple phenotypic traits by populating conformations that favor interactions with other network modules. It also suggests how to identify such mutations and their signaling consequences. Biophysics offers principles and strategies that can help precision medicine push the boundaries to transform our insight into biological processes and the practice of personalized medicine. By contrast, Bphenotypic drug discovery,^which capitalizes on physiological cellular conditions and first-in-class drug discovery, may not capture the proper molecular variant. This is because variants of the same protein can express more than one phenotype, and a phenotype can be encoded by several variants.

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“…The hits identified here may therefore serve as good starting points for development of tool compounds/new drugs targeting this enzyme. Ayotte et al (2018) used a hybrid strategy incorporating aspects of a fragment-based approach and a phenotypic screen, to identify fragments with leishmanicidal activity. From an initial set of 8000 fragments, a library of 1604 fragments was compiled.…”

Section: Screening Fragments By X-ray Crystallography To Identify Novel Chemical Starting Points For Antileishmanial Drug Designmentioning

confidence: 99%

The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases

Spry¹,

Coyne²

2019

Medicinal Chemistry of Neglected and Tropical Diseases

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† At of the time of publication, the WHO NTD portfolio includes: (1) Buruli ulcer, (2) Chagas disease, (3) Dengue and Chikungunya, (4) Dracunculiasis, (5) Echinococcosis, (6) Foodborne trematodiases, (7) Human African trypanosomiasis, (8) Leishmaniasis, (9) Leprosy, (10) Lymphatic filariasis, (11) Mycetoma, chromoblastomycosis and other deep mycoses, (12) Onchocerciasis, (13) Rabies, (14) Scabies and other ectoparasites, (15) Schistosomiasis, (16) Soil-transmitted helminthiases, (17) Snakebite envenoming, (18) Taeniasis, (19) Trachoma, and (20) Yaws.

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Fragment‐Based Phenotypic Lead Discovery: Cell‐Based Assay to Target Leishmaniasis

Cited by 13 publications

References 63 publications

Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

Precision medicine review: rare driver mutations and their biophysical classification

The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases

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