Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists.

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) hold great therapeutic potential, but their activity is hindered by poor drug-like properties that restrict cytosolic bioavailability. Here, this challenge is addressed through the synthesis and evaluation of a novel series of PEGMA-co-DEAEMA-co-BMA copolymers with pH-responsive, membrane-destabilizing activity to enhance intracellular delivery of the CDN, cGAMP. Copolymers are synthesized with PEGMA of two different molecular weights (300 and 950 Da) and over a range of PEG mass fraction and polymer molecular weight, and relationships between copolymer structure, self-assembly, endosomal escape, and cGAMP activity are elucidated. A subset of polymers that self-assembled into 50-800 nm nanoparticles is identified, which can be loaded with cGAMP via a simple mixing strategy, resulting in significantly enhanced immunostimulatory activity. Increased cGAMP activity is found to be highly correlated with the capacity of carriers to enhance intracellular CDN uptake and to promote endosomal destabilization, findings that establish efficient cytosolic delivery as a criterion for CDN carriers. Additionally, it is demonstrated that a lead CDN carrier formulation can enhance STING activation in vivo in a model of intratumoral immunotherapy. Collectively, these investigations demonstrate the utility of PEGMA-co-DEAEMA-co-BMA copolymers as carriers for CDNs and potentially other cytosolically-acting drug cargo.

The affinity of RSK for cylitol analogues of SL0101 is critically dependent on the B-ring C-4'-hydroxy.

Five cyclitol analogues of SL0101 with variable substitution at the C-4' position (i.e., OH, Cl, F, H, OMe) were synthesized. The series of analogues were evaluated for their ability to inhibit p90 ribosomal S6 kinase (RSK) activity. The study demonstrated the importance of the B-ring C-4' hydroxy group for RSK1/2 inhibition.

Application of capillary electrophoresis combined with conductometric and UV detection to monitor meteorite simulant bioleaching by Acidithiobacillus ferrooxidans.

The importance of microorganisms and biotechnology in space exploration and future planets colonization has been discussed in the literature. Meteorites are interesting samples to study microbe-mineral interaction focused on space exploration. The chemolithotropic bacterium Acidithiobacillus ferrooxidans has been used as model to understand the iron and sulfur oxidation. In this work, capillary electrophoresis with capacitively coupled contactless conductivity detection and UV detection was used to monitor bacterial growth in a meteorite simulant by measuring the conversion of Fe2+ into Fe+3 . The effect of Co2+ and Ni2+ (metals also found in meteorites) on the bacterial growth was also evaluated. The presented method allowed the analyses of all metals in a single run (less than 8 min). The background electrolyte was composted of 10 mmol/L α-hydroxyisobutyric acid/Histidine. For comparison purpose, the samples were also analyzed by UV-Vis spectrophotometry. The Fe2+ conversion into Fe3+ by A. ferrooxidans was observed up to 36 h with the growth rate constant of 0.19/h and 0.21/h in Tuovinen and Kelly (T&K) and in meteorite simulant media, respectively. The developed method presents favorable prospect to monitor the growth of other chemolithotropic microorganisms for biotechnology applications.