Biological activity

Résumé

In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by the other constituents. Among the various properties of chemical compounds, pharmacological/biological activity plays a crucial role since it suggests uses of the compounds in the medical applications. However, chemical compounds may show some adverse and toxic effects which may prevent their use in medical practice. Biological activity is usually measured by a bioassay and the activity is generally dosage-dependent, which is investigated via dose-response curves. Further, it is common to have effects ranging from beneficial to adverse for one substance when going from low to high doses. Activity depends critically on fulfillment of the ADME criteria. To be an effective drug, a compound not only must be ac

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Crossing properties of soil saturation, defined as the duration and excursion of soil saturation below and above certain thresholds, are key variables to ecosystem functioning and evolution by primarily influencing the plant and soil microbes physiological dynamics. Under climate change, the variability in the precipitation patterns is expected to be more ubiquitous and directly translate to a shift in soil saturation levels. This, in turn, will influence crossing properties of soil saturation and thus be expected to leave a mark on ecosystems. However, the lack of a deep understanding of the links between biological processes and the change in soil saturation patterns hinders foretelling the impact of climate variability on ecohydrological systems even at the smallest scale, that is, the level of a single plant.To that end, this thesis presents experimental results from laboratory soil column experiments and extensive computational studies on the interactions between soil saturation and biological activities, that is, plants and microbes. To this aim, the depth-time soil saturation patterns are mapped by means of modeling the transport processes of relevance and experimental tools at a minimal hydrological control volume in search for upscaling methods. In this context, two modeling approaches can be employed. Physically based models that explicitly represent transport processes with high costs of application at larger scales. Age-based models that rely on generic functions with a focus on time past since arrival, that is, the age of event water in the storage. This thesis work combines models (HYDRUS-1D as physically based and tran-SAS as age-based) with soil column experimental data and Bayesian inference methods to explore the links between age characteristics and transport processes. In this thesis, data from four different experimental designs on monthly to yearly timescale under varied environmental conditions are examined in terms of tracer type, precipitation pattern, vegetation, soil type, resolution and type of collected data. Of the modeled data, two sets of results from specific experiments were carried out within the framework of this thesis.This thesis addresses also the role of the balance between dispersive and convective forces, known as Péclet number, in controlling the shape of age functions in drainage. While sole reliance on drainage flow and tracer data (reflective of Péclet number) suffice to capture age dynamics in drainage, un- certainties may arise for predictions on (evapo)transpiration. This thesis deals also with the role of root distributions as controls in determining the age to root uptake and shows plants with similar uniform-equivalent root distribution render very similar age dynamics. It was shown in this thesis that nitrate consumption by microbes can be linked to age characteristics of a conservative tracer and that the relation between microbial respiration and soil saturation may bear more complexity than is currently integrated in most models. Overall, this thesis lays steps to the development of modeling tools with high predictive power for soil saturation by originating upscaling methods and bridging the gaps between physically based and age-based models with a view on the consequences of (possi- bly changing) variable soil saturation on adaptations of microbial communities and their metabolic product.

EPFL2022

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Macrophage migration inhibitory factor (MIF) is a major mediator in innate immunity and inflammation and a potential therapeutic target in multiple inflammatory, infectious and autoimmune diseases including cancer. Current therapeutic strategies for targeting MIF focus on modulating its biological activities using anti-MIF neutralizing antibodies or developing inhibitors of its tautomerase activity. Although the identity of its natural substrate remains unknown, several small molecule inhibitors have been reported to be effective inhibitors of MIF tautomerase activity in vitro. All these inhibitors were identified by rational design and structure-activity studies based on the structure of the catalytic site and/or non physiologic substrates of MIF. The lack of suitable high-throughput screening (HTS) assays has hindered the screening of chemical libraries and discovery of more diverse inhibitors. Motivated by the goal of discovering diverse classes of MIF inhibitors that modulate MIF activity specific targeting of its biochemical, conformation and quaternary structure properties, both activity based endpoint and kinetic HTS assays were developed, optimized and performed on diverse set of libraries. Using the endpoint assay, out of 15440 compounds screened, twelve novel inhibitors of MIF's catalytic activity (∼ 0.1% hit rate) with IC50s in the range of 1.5 to 15.5 µM were identified and validated. The interaction site and mechanism of action of all these inhibitors were defined using structure activity studies and a battery of biochemical and biophysical methods, including mass spectrometry, light scattering, and NMR. The effect on MIF biological activities was also examined on MIF-mediated glucocorticoid overriding and MIF-induced Akt phosphorylation. Using the kinetic-based activity assay, we screened 80,000 small molecules and identified and validated thirteen novel inhibitors of MIF catalytic activity with inhibition constant (Ki,app) values ranging from 0.5 to 13 µM. According to the structure and potency some of these molecules could be of great therapeutic potential. The MIF inhibitors emerging from these studies could be divided into four classes: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro1 which could be classified into 5 groups; 2) a novel class of catalytic site inhibitors, 3) a class of trimer destabilizing inhibitors. These findings demonstrate the potential of HTS assays as attractive means to identify novel classes of MIF inhibitors as lead drug candidates and/or chemical tools for elucidating the biochemical and structural bases underlying the multifunctionality of MIF's in health and disease. Having these molecules in hand, will advance our understanding of protein-protein interactions mechanism for MIF oligomerization and may help to elucidate the role of MIF enzymatic activity in health and disease.

EPFL2010

Chargement

Converting disulfide bridges in native peptides to stable methylene thioacetals

Nicolai Cramer, Christopher Matthew Bandeli Kourra

Disulfide bridges play a crucial role in defining and rigidifying the three-dimensional structure of peptides. However, disulfides are inherently unstable in reducing environments. Consequently, the development of strategies aiming to circumvent these deficiencies - ideally with little structural disturbance - are highly sought after. Herein, we report a simple protocol converting the disulfide bond of peptides into highly stable methylene thioacetal. The transformation occurs under mild, biocompatible conditions, enabling the conversion of unprotected native peptides into analogues with enhanced stability. The developed protocol is applicable to a range of peptides and selective in the presence of a multitude of potentially reactive functional groups. The thioacetal modification annihilates the reductive lability and increases the serum, pH and temperature stability of the important peptide hormone oxytocin. Moreover, it is shown that the biological activities for oxytocin are retained.

Royal Soc Chemistry2016

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