Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

7th Drug hypersensitivity meeting: part two

No abstract availabl

Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

© 2014 Diaz et al. In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.Peer Reviewe

The burden of allergens in surimi-based products diminishes with industrial processing

2 pags, 2 figs. -- Supplementary material is available at the Publisher's webThis research was funded by Spanish Ministry of Science and Innovation (CDTI-CIEN Tolera grant) . The funders had no role in any of the following: study design; data collection, analyses, or interpretation; writing of the manuscript; decision to publish the results.Peer reviewe

Physician&apos;s appraisal vs documented signs and symptoms in the interpretation of food challenge tests: The EuroPrevall birth cohort

Background: Blinded food challenges are considered the current gold standard for the diagnosis of food allergies. We used data from a pan-European multicenter project to assess differences between study centers, aiming to identify the impact of subjective aspects for the interpretation of oral food challenges. Methods: Nine study centers of the EuroPrevall birth cohort study about food allergy recruited 12 049 newborns and followed them for up to 30 months in regular intervals. Intensive training was conducted and every center visited to ensure similar handling of the protocols. Suspected food allergy was clinically evaluated by double-blind, placebo-controlled food challenges using a nine dose escalation protocol. The primary challenge outcomes based on physician&apos;s appraisal were compared to documented signs and symptoms. Results: Of 839 challenges conducted, study centers confirmed food allergy in 15.6% to 53.6% of locally conducted challenges. Centers reported 0 to 16 positive placebo challenges. Worsening of eczema was the most common sign when challenged with placebo. Agreement between documented objective signs and the challenge outcome assigned by the physician was heterogeneous, with Cohen&apos;s kappa spanning from 0.42 to 0.84. Conclusions: These differences suggest that the comparison of food challenge outcomes between centers is difficult despite common protocols and training. We recommend detailed symptom assessment and documentation as well as objective sign-based challenge outcome algorithms to assure accuracy and comparability of blinded food challenges. Training and supervision of staff conducting food challenges is a mandatory component of reliable outcome data. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd

Physician&apos;s appraisal vs documented signs and symptoms in the interpretation of food challenge tests: The EuroPrevall birth cohort

Background: Blinded food challenges are considered the current gold standard for the diagnosis of food allergies. We used data from a pan-European multicenter project to assess differences between study centers, aiming to identify the impact of subjective aspects for the interpretation of oral food challenges. Methods: Nine study centers of the EuroPrevall birth cohort study about food allergy recruited 12 049 newborns and followed them for up to 30 months in regular intervals. Intensive training was conducted and every center visited to ensure similar handling of the protocols. Suspected food allergy was clinically evaluated by double-blind, placebo-controlled food challenges using a nine dose escalation protocol. The primary challenge outcomes based on physician&apos;s appraisal were compared to documented signs and symptoms. Results: Of 839 challenges conducted, study centers confirmed food allergy in 15.6% to 53.6% of locally conducted challenges. Centers reported 0 to 16 positive placebo challenges. Worsening of eczema was the most common sign when challenged with placebo. Agreement between documented objective signs and the challenge outcome assigned by the physician was heterogeneous, with Cohen&apos;s kappa spanning from 0.42 to 0.84. Conclusions: These differences suggest that the comparison of food challenge outcomes between centers is difficult despite common protocols and training. We recommend detailed symptom assessment and documentation as well as objective sign-based challenge outcome algorithms to assure accuracy and comparability of blinded food challenges. Training and supervision of staff conducting food challenges is a mandatory component of reliable outcome data. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd

Risk Factors for Hen&apos;s Egg Allergy in Europe: EuroPrevall Birth Cohort

Background: Hen&apos;s egg is one of the commonest causes of food allergy, but there are little data on its risk factors. Objective: To assess the risk factors, particularly eczema, for hen&apos;s egg allergy in the EuroPrevall birth cohort. Methods: In the pan-European EuroPrevall birth cohort, questionnaires were undertaken at 12 and 24 months or when parents reported symptoms. Children with suspected egg allergy were invited for skin prick testing, specific IgE assessment, and double-blind, placebo-controlled food challenge (DBPCFC) as indicated. Each egg allergy case (positive DBPCFC or egg-induced anaphylaxis) was allocated up to 2 age- and country-matched controls. Results: A total of 12,049 infants were recruited into the EuroPrevall birth cohort, and 9,336 (77.5%) were followed until 2 years. A total of 86 infants had egg allergy (84 by DBPCFC) and were matched with 140 controls. Independently associated with egg allergy were past/current eczema (adjusted odds ratio, 9.21; 95% CI, 2.65-32.04), Scoring Atopic Dermatitis (1.54 per 5 units; 1.28-1.86), antibiotics in the first week of life (6.17; 1.42-26.89), and current rhinitis (3.02; 1.04-8.78). Increasing eczema severity was associated with an increasing likelihood of egg allergy. Eczema was reported to have started 3.6 (SE, 0.5) months before egg allergy. Age of introduction of egg into the diet was not associated with egg allergy. Conclusions: Similar to peanut allergy, eczema was strongly associated with egg allergy development and the association increased with increasing eczema severity. The age of introduction of dietary egg was not a risk factor. The potential role of antibiotics in early life as a risk factor for egg allergy needs further examination. © 201