Biology subjects

Schreiber, C.

Publications and source records attributed to Schreiber, C..

4 recordsLinked to original sources

bioRxiv2024

Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55 as a potent dual EPHA2/GAK inhibitor. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells, mainly via its EPHA2 activity, and is therefore a promising candidate for further optimization of its activity against dengue virus.

biochemistry↗

bioRxiv2022

On multistability and constitutive relations of cell motion on Fibronectin lanes

Cell motility on flat substrates exhibits multistability between steady and oscillatory morphodynamics, spread and moving states, the biphasic adhesion-velocity relation, and the universal correlation between speed and persistence (UCSP) as simultaneously observed phenomena. Their universality and concurrency suggest a unifying mechanism to exist causing all of them. We search for that mechanism by investigating trajectories of MDA-MB-231 cells on Fibronectin lanes. We also find multistability caused by the clutch mechanism of retrograde flow. Control of the clutch parameters by integrin signalling causes the biphasic adhesion-velocity relation. Protrusion competition based on the clutch causes direction reversal events, the statistics of which explains the UCSP. We suggest that F-actin polymerisation, clutch mechanism of retrograde flow, protrusion competition via membrane tension and drag forces cause the multistability and dynamic cell states, state transition statistics causes the UCSP and the control of this dynamic system by integrin signalling entails the adhesion-velocity relation.

biophysics↗

bioRxiv2019

Area and Geometry Dependence of Cell Migration in Asymmetric Two-State Micropatterns

Micro-structured surfaces provide a unique framework to probe cell migration and cytoskeletal dynamics in a standardized manner. Here, we report on the steady-state occupancy probability of cells in asymmetric two-state microstructures that consist of two fibronectin-coated adhesion sites connected by a thin guidance cue. In these dumbbell-like structures, cells transition between the two sites in a repeated and stochastic manner and average dwell times in the respective microenvironments are determined from the cell trajectories. We study the dynamics of human breast carcinoma cells (MDA-MB-231) in these microstructures as a function of area, shape and orientation of the adhesion sites. On square adhesive sites with different areas, we find that the occupancy probability ratio is directly proportional to the ratio of corresponding adhesion site areas. Sites of equal area but different shape lead to equal occupancy, if shapes are isotropic, e.g. squared or circular. In contrast, an asymmetry in the occupancy is induced by anisotropic shapes like rhombi, triangles or rectangles that enable motion in the direction perpendicular to the transition axis. Analysis of the 2D motion of cells between two rectangles with orthogonal orientation suggests that cellular transition rates depend on the cell polarisation induced by anisotropic micropatterns. Taken together, our results illustrate how two-state-micropatterns provide a dynamic migration assay with distinct dwell times and relative cell occupancy as readouts, which may potentially be useful to probe cell-microenvironment interactions.

biophysics↗

bioRxiv2019

Quasi-periodic migration of single cells on short microlanes

Cell migration on microlanes represents a suitable and simple platform for the exploration of the molecular mechanisms underlying cell cytoskeleton dynamics. Here, we report on the quasi-periodic movement of cells confined in stripe-shaped microlanes. We observe persistent polarized cell shapes and directed pole-to-pole motion within the microlanes. Cells depolarize at one end of a given microlane, followed by delayed repolarization towards the opposite end. We analyze cell motility via the spatial velocity distribution, the velocity frequency spectrum and the reversal time as a measure for depolarization and spontaneous repolarization of cells at the microlane ends. The frequent encounters of a boundary in the stripe geometry provides a robust framework for quantitative investigations of the cytoskeleton protrusion and repolarization dynamics. In a first advance to rigorously test physical models of cell migration, we find that the statistics of the cell migration is recapitulated by a Cellular Potts model with a minimal description of cytoskeleton dynamics. Using LifeAct-GFP transfected cells and microlanes with differently shaped ends, we show that the local deformation of the leading cell edge in response to the tip geometry can locally either amplify or quench actin polymerization, while leaving the average reversal times unaffected.

biophysics↗