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10 years into the resurgence of covalent drugs.

ABSTRACT: In the first decade of targeted covalent inhibition, scientists have successfully reversed the previous trend that had impeded the use of covalent inhibition in drug development. Successes in the clinic, mainly in the field of kinase inhibitors, are existing proof that safe covalent inhibitors can be designed and employed to develop effective treatments. The case of KRAS_G12C covalent inhibitors entering clinical trials in 2019 has been among the hottest topics discussed in drug discovery, raising expectations for the future of the field. In this perspective, an overview of the milestones hit with targeted covalent inhibitors, as well as the promise and the needs of current research, are presented. While recent results have confirmed the potential that was foreseen, many questions remain unexplored in this branch of precision medicine.

SUBMITTER: De Vita E

PROVIDER: S-EPMC8356679 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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10 years into the resurgence of covalent drugs.

De Vita Elena E

Future medicinal chemistry 20201204 2

In the first decade of targeted covalent inhibition, scientists have successfully reversed the previous trend that had impeded the use of covalent inhibition in drug development. Successes in the clinic, mainly in the field of kinase inhibitors, are existing proof that safe covalent inhibitors can be designed and employed to develop effective treatments. The case of KRAS<sub>G12C</sub> covalent inhibitors entering clinical trials in 2019 has been among the hottest topics discussed in drug discov ...[more]

PMID: 33275063

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Project description:Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 during 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/SumiShield). To quantify the magnitude of the resurgence, investigate causes, and evaluate the impact of a shift back to IRS with Actellic in 2023, we assessed changes in malaria metrics in regions within and near Tororo District. Malaria surveillance data from Nagongera Health Center, Tororo District was included from 2011-2023. In addition, a cohort of 667 residents from 84 houses was followed from August 2020 through September 2023 from an area bordering Tororo and neighboring Busia District, where IRS has never been implemented. Cohort participants underwent passive surveillance for clinical malaria and active surveillance for parasitemia every 28 days. Mosquitoes were collected in cohort households every 2 weeks using CDC light traps. Female Anopheles were speciated and tested for sporozoites and phenotypic insecticide resistance. Temporal comparisons of malaria metrics were stratified by geographic regions. At Nagongera Health Center average monthly malaria cases varied from 419 prior to implementation of IRS; to 56 after 5 years of IRS with Bendiocarb and Actellic; to 1591 after the change in IRS to Fludora Fusion/SumiShield; to 155 after a change back to Actellic. Among cohort participants living away from the border in Tororo, malaria incidence increased over 8-fold (0.36 vs. 2.97 episodes per person year, p<0.0001) and parasite prevalence increased over 4-fold (17% vs. 70%, p<0.0001) from 2021 to 2022 when Fludora Fusion/SumiShield was used. Incidence decreased almost 5-fold (2.97 vs. 0.70, p<0.0001) and prevalence decreased by 39% (70% vs. 43%, p<0.0001) after shifting back to Actellic. There was a similar pattern among those living near the border in Tororo, with increased incidence between 2021 and 2022 (0.93 vs. 2.40, p<0.0001) followed by a decrease after the change to Actellic (2.40 vs. 1.33, p<0.001). Among residents of Busia, malaria incidence did not change significantly over the 3 years of observation. Malaria resurgence in Tororo was temporally correlated with the replacement of An. gambiae s.s. by An. funestus as the primary vector, with a marked decrease in the density of An. funestus following the shift back to IRS with Actellic. In Busia, An. gambiae s.s. remained the primary vector throughout the observation period. Sporozoite rates were approximately 50% higher among An. funestus compared to the other common malaria vectors. Insecticide resistance phenotyping of An. funestus revealed high tolerance to clothianidin, but full susceptibility to Actellic. A dramatic resurgence of malaria in Tororo was temporally associated with a change to clothianidin-based IRS formulations and emergence of An. funestus as the predominant vector. Malaria decreased after a shift back to IRS with Actellic. This study highlights the ability of malaria vectors to rapidly circumvent control efforts and the importance of high-quality surveillance systems to assess the impact of malaria control interventions and generate timely, actionable data.

Project description:ImportancePhysical activity may promote healthy brain development in children, but previous research was predominantly cross-sectional and included small samples, providing limited knowledge.ObjectiveTo investigate the longitudinal associations of physical activity with brain morphology changes.Design, setting, and participantsA 4-year longitudinal population-based cohort study in Rotterdam, the Netherlands, embedded in Generation R, a cohort from fetal life onward. From the women enrolled during pregnancy, children who had repeated measures of brain structure at ages 10 (range 8 to 12) years and 14 (range 13 to 15) years were included. Data were collected from March 2013 to November 2015 (baseline) and from October 2016 to January 2020 (follow-up). Data were analyzed from April to December 2022.ExposureAt age 10 years, both the child and their primary caregiver reported the child's levels of physical activity with regard to sport participation, outdoor play, and total physical activity. Primary analyses were based on an average multi-informant report.Main outcomes and measuresBrain morphology was quantified by magnetic resonance imaging. Hypothesized regions of interest were the bilateral amygdala and hippocampal volumes. Global brain measures were studied to test the specificity of the hypothesis.ResultsData were available for 1088 children (566 girls [52%]; 693 [64%] Dutch). Their mean (SD) age at baseline was 10.1 (0.6) years. For amygdala volume change, positive associations with multi-informant reports of total physical activity (β = 2.6; 95% CI, 0.3-4.9) were found. Total physical activity was associated with hippocampal volume increases only when reported by the child (β = 3.1; 95% CI, 0.4-5.8). No robust associations with global brain measures were found.Conclusions and relevanceIn this cohort study of 1088 children, more physical activity at 10 years was consistently associated with an increase in amygdala volume in children aged 10 to 14 years. Physical activity and increases in hippocampal volume were found using child reports of physical activity only. These findings suggest physical activity in late childhood was prospectively associated with volumetric changes in specific subcortical structures, but not to global brain development, from late childhood to early adolescence. These findings may inform the design of future public health interventions to best facilitate neurodevelopment with physical activity.

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10 years into the resurgence of covalent drugs.

Publications

10 years into the resurgence of covalent drugs.

Similar Datasets

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