Publications by authors named "Kevin D Read"

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections.

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Cryptosporidiosis is a diarrheal disease caused by infection with spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population.

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Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction.

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A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems.

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Chagas disease, caused by the protozoan parasite , affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required.

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The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D ranging from 2.

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Article Synopsis
  • * Pks13 has been identified as a crucial target for developing new growth inhibitors for TB, with prior attempts using benzofuran inhibitors halted due to safety concerns.
  • * Researchers have discovered a novel series of oxadiazole inhibitors that effectively target Pks13, showing better potency and safety profiles compared to previous compounds.
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Working in drug discovery is difficult for many institutions due to the need for resources, funding, and in-country expertise. The Wellcome Centre for Anti-Infective Research (WCAIR) is responding to the unmet training needs for individuals/institutions working in drug discovery in low-middle income countries. Through their training program, individuals can undertake a practical placement, either online or at the center, with access to a dedicated trainer from their field of research.

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There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the proteasome. A related analogue, active against , showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated.

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Article Synopsis
  • While treatments for human African trypanosomiasis (HAT) have advanced, new drugs are still needed as eradication becomes feasible.
  • Researchers developed 2,4-diaminothiazoles that show strong effectiveness against the parasite causing HAT, using phenotypic screening to enhance their drug-like properties.
  • Despite promising initial results, the compounds failed to effectively treat the severe stage of the disease due to a shift from a destructive to a static action mechanism, highlighting a need for drugs that actively kill the parasite.
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Article Synopsis
  • * The meeting highlighted that while PZQ is the only available treatment for all schistosomiasis species, it often fails to completely eliminate the infection, particularly in juvenile worms, and may face resistance issues.
  • * Experts discussed the essential criteria for developing new anti-schistosomal medications and potential drug discovery pathways to improve treatment options for this public health concern.
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The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against () 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as stability in human and rat microsomes.

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Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described.

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There is a need for non-hormonal contraceptives. One area that needs further investigation is the development of male contraceptives. Comparatively little is understood about potential drug targets in men to achieve a reversible contraceptive effect.

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Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinical development pipeline is particularly sparse for Chagas disease. In this Review, we describe recent advances in our understanding of the biology of the causative pathogens, particularly from the drug discovery perspective, and we explore the progress that has been made in the development of new drug candidates and the identification of promising molecular targets.

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Chagas disease caused by the protozoan is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages; thus, there is a need to find improved treatments.

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Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability.

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African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites and is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis.

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Study Question: Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery?

Summary Answer: An HTS platform identified a large number of compounds that enhanced sperm motility.

What Is Known Already: Several efforts to find small molecules modulating sperm function have been performed but none have used high-throughput technology.

Study Design, Size, Duration: Healthy donor semen samples were used and samples were pooled (3-5 donors per pool).

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Article Synopsis
  • Due to rising drug resistance in tuberculosis patients, there is a critical demand for new drugs targeting novel mechanisms to bypass existing resistance.
  • Benzofuran has shown potential as a TB treatment by targeting the thioesterase domain of Pks13, but it poses a risk of inhibiting the hERG cardiac ion channel, leading to heart irregularities.
  • Although the research team improved the compound's safety profile, they ultimately halted development due to persistent cardiac concerns, yet the study supports Pks13 as a promising target for new TB drugs and encourages exploring different chemical structures.
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Twenty eight new N,N-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance.

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There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 () as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with efficacy, which was hampered by poor solubility and genotoxicity.

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