Colloidal aggregators in biochemical SARS-CoV-2 repurposing screens

To fight the SARS-CoV-2 pandemic, much effort has been directed toward drug repurposing, testing investigational and approved drugs against several viral or human proteins in vitro. Here we investigate the impact of colloidal aggregation, a common artifact in early drug discovery, in these repurposing screens. We selected 56 drugs reported to be active in biochemical assays and tested them for aggregation by both dynamic light scattering and by enzyme counter screening with and without detergent; seventeen of these drugs formed colloids at concentrations similar to their literature reported IC50s. To investigate the occurrence of colloidal aggregators more generally in repurposing libraries, we further selected 15 drugs that had physical properties resembling known aggregators from a common repurposing library, and found that 6 of these aggregated at micromolar concentrations. An attraction of repurposing is that drugs active on one target are considered de-risked on another. This study suggests not only that many of the drugs repurposed for SARS-CoV-2 in biochemical assays are artifacts, but that, more generally, when screened at relevant concentrations, drugs can act artifactually via colloidal aggregation. Understanding the role of aggregation, and detecting its effects rapidly, will allow the community to focus on those drugs and leads that genuinely have potential for treating COVID-19.Abstract FigureTable of Contents Graphic

Self-Assembled Structures of Colloidal Dimers and Disks on a Spherical Surface

We study self-assembly on a spherical surface of a model for a binary mixture of amphiphilic dimers in the presence of guest particles via Monte Carlo (MC) computer simulation. All particles had a hard core, but one monomer of the dimer also interacted with the guest particle by means of a short-range attractive potential. We observed the formation of aggregates of various shapes as a function of the composition of the mixture and of the size of guest particles. Our MC simulations are a further step towards a microscopic understanding of experiments on colloidal aggregation over curved surfaces, such as oil droplets.

Colloidal aggregation in anisotropic liquid crystal solvent

The mutual attraction between colloidal particles in an anisotropic fluid, such as the nematic liquid crystal phase, leads to the formation of hierarchical aggregate morphologies distinct from those that tend...

Molecular Dynamics Simulation of the Interaction between Common Metal Ions and Humic Acids

Humic acids (HAs) have important environmental and geochemical effects on soil, water environments and sediment. HAs strongly complex some metal ions, which affects the migration of metal ions and the colloidal aggregation of HA. Here, the complexation of Ca2+ and Mg2+ with HA in aqueous solution under neutral conditions has been systematically studied by molecular dynamics (MD) simulation. The results show that the aggregation of HA is caused by the complexation of HA and metal ions, mainly due to the intermolecular bridging between Ca2+, Mg2+ and COO− groups. Monodentate and bidentate coordinations have been found between Ca2+ and COO− groups of different HA molecules in the same simulation system. Mg2+ only has a monodentate coordination with COO− group.

Transient Colloid Assembly by Fuel-Driven Modulation of Depletion Interactions

In biology, energy stored in chemical fuels is used to drive processes energetically uphill, enabling the highly dynamic behavior of living organisms. The out-of-equilibrium behavior can propagate from molecular reaction networks to the micro- and macroscopic scale. These natural phenomena have sparked the design of man-made out of equilibrium chemical reaction networks (CRNs) and dissipative assembly systems with hydrogels, (supra)polymers, vesicles/micelles and colloids. In colloidal systems, the assembly process is typically controlled by balancing the interaction forces. Here, we use a polymeric depletant integrated in a fuel driven esterification CRN to induce transient colloidal assembly. The polymer undergoes a temporal coil-globule transition upon acetylation by the chemical fuel. In the random coil conformation it acts as depletant agent for the silica colloids, promoting colloidal aggregation. As compact globule, the polymer loses its<br>depletant characteristics. During the fuel cycle the polymer cyclically transitions from one form to the other, directly influencing colloidal aggregation and redispersion. Thus, a fuel-driven CRN on the molecular scale results in a microscopic response with a transient colloidal depletion cycle. Overall, the time-dependent propagation of out-of-equilibrium activity across length scales presented here, offers opportunities to design responsive materials with life like properties.

Transient Colloid Assembly by Fuel-Driven Modulation of Depletion Interactions

In biology, energy stored in chemical fuels is used to drive processes energetically uphill, enabling the highly dynamic behavior of living organisms. The out-of-equilibrium behavior can propagate from molecular reaction networks to the micro- and macroscopic scale. These natural phenomena have sparked the design of man-made out of equilibrium chemical reaction networks (CRNs) and dissipative assembly systems with hydrogels, (supra)polymers, vesicles/micelles and colloids. In colloidal systems, the assembly process is typically controlled by balancing the interaction forces. Here, we use a polymeric depletant integrated in a fuel driven esterification CRN to induce transient colloidal assembly. The polymer undergoes a temporal coil-globule transition upon acetylation by the chemical fuel. In the random coil conformation it acts as depletant agent for the silica colloids, promoting colloidal aggregation. As compact globule, the polymer loses its<br>depletant characteristics. During the fuel cycle the polymer cyclically transitions from one form to the other, directly influencing colloidal aggregation and redispersion. Thus, a fuel-driven CRN on the molecular scale results in a microscopic response with a transient colloidal depletion cycle. Overall, the time-dependent propagation of out-of-equilibrium activity across length scales presented here, offers opportunities to design responsive materials with life like properties.

Tetraethyl Orthosilicate-Based Hydrogels for Drug Delivery—Effects of Their Nanoparticulate Structure on Release Properties

Tetraethyl orthosilicate (TEOS)-based hydrogels, with shear stress response and drug releasing properties, can be formulated simply by TEOS hydrolysis followed by volume corrections with aqueous solvents and pH adjustments. Such basic thixotropic hydrogels (thixogels) form via the colloidal aggregation of nanoparticulate silica. Herein, we investigated the effects of the nanoparticulate building blocks on the drug release properties of these materials. Our data indicate that the age of the hydrolyzed TEOS used for the formulation impacts the nanoparticulate structure and stiffness of thixogels. Moreover, the mechanism of formation or the disturbance of the nanoparticulate network significantly affects the release profiles of the incorporated drug. Collectively, our results underline the versatility of these basic, TEOS-only hydrogels for drug delivery applications.