The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how varying physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was critical for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular platform in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

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Agonists of immune cell receptors direct innate and adaptive immunity. These agonists range in size and complexity from small molecules to large macromolecules. Here, agonists of a class of immune cell receptors known as the Toll-Like Receptors (TLRs) are highlighted focusing on the distinctive molecular moieties that pertain to receptor binding and activation. How the structure and combined chemical signals translate into a variety of immune responses remain major questions in the field. In this structure-focused review, we outline potential areas where the tools of chemical biology could help decipher the emerging molecular codes that direct immune stimulation.

Metal fluorides (MF) are one of the most attractive cathode candidates for Li ion batteries (LIBs) due to their high conversion potentials with large capacities. However, only a limited number of synthetic methods, generally involving highly toxic or inaccessible reagents, currently exist, which has made it difficult to produce well-designed nanostructures suitable for cathodes; consequently, harnessing their potential cathodic properties has been a challenge. Herein, we report a new bottom-up synthetic method utilizing ammonium fluoride (NHF) for the preparation of anhydrous MF (CuF, FeF, and CoF)/mesoporous carbon (MSU-F-C) nanocomposites, whereby a series of metal precursor nanoparticles preconfined in mesoporous carbon were readily converted to anhydrous MF through simple heat treatment with NHF under solventless conditions. We demonstrate the versatility, lower toxicity, and efficiency of this synthetic method and, using XRD analysis, propose a mechanism for the reaction. All MF/MSU-F-C prepared in this study exhibited superior electrochemical performances, through conversion reactions, as the cathode for LIBs. In particular, FeF/MSU-F-C maintained a capacity of 650 mAh g across 50 cycles, which is ∼90% of its initial capacity. We expect that this facile synthesis method will trigger further research into the development of various nanostructured MF for use in energy storage and other applications.

State-of-the art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high energy light (l < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red light (l = 660 nm) photoredox catalysis and its use in photocatalyzed proximity labeling. We demonstrate that aryl azides are converted to triplet nitrenes via a novel redox-centric mechanism and show that its spatially localized-formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labeling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumor selective expression with EpCAM.

The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-κB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population.

Over half of new therapeutic approaches fail in clinical trials due to a lack of target validation. As such, the development of new methods to improve and accelerate the identification of cellular targets, broadly known as target ID, remains a fundamental goal in drug discovery. While advances in sequencing and mass spectrometry technologies have revolutionized drug target ID in recent decades, the corresponding chemical-based approaches have not changed in over 50 y. Consigned to outdated stoichiometric activation modes, modern target ID campaigns are regularly confounded by poor signal-to-noise resulting from limited receptor occupancy and low crosslinking yields, especially when targeting low abundance membrane proteins or multiple protein target engagement. Here, we describe a broadly general platform for photocatalytic small molecule target ID, which is founded upon the catalytic amplification of target-tag crosslinking through the continuous generation of high-energy carbene intermediates via visible light-mediated Dexter energy transfer. By decoupling the reactive warhead tag from the small molecule ligand, catalytic signal amplification results in unprecedented levels of target enrichment, enabling the quantitative target and off target ID of several drugs including (+)-JQ1, paclitaxel (Taxol), dasatinib (Sprycel), as well as two G-protein-coupled receptors—ADORA2A and GPR40.

Polydimethyl siloxane (PDMS) is the most widely used polymer in microfl uidic devices. Microfl uidic devices are used in all ranges of science. The microstructure of a microfl uidic device infl uences its effi ciency. One method for controlling microstructure is through wet etching. A particularly common etchant is tetrabutylammonium fl uoride (TBAF). This report shows that the etching rate of PDMS by a TBAF solution is controlled by the solvent in use. This report presents that solvent dictates interplay between the reactivity of the naked fl uoride with the Si O bonds in the polymer chain and the solubility of the polymer chains. Both high reactivity and accessibility are necessary for a high etching rate. This gives a simple method to control the etching rate of PDMS and by that the microstructure of the microfl uidic device.Dr. M. Kleiman, K. A. Ryu, Prof. A. P. Esser-Kahn Chemistry Department Natural Sciences II Irvine, CA 92697 , USA E-mail: aesserka@uci.edu One of the most common wet etchants for PDMS is tetrabutylammonium fl uoride (TBAF) [19][20][21] -owing to its rapid generation of "naked" fl uoride. Previously, researchers controlled the etching rate of PDMS by varying the fl ow rate and the concentration of TBAF. [ 22 ] They reported a maximum increase of 100% in etching rate by increasing fl ow rate as well as a structural change that depended on TBAF concentration. Here we show an increased etching rate of PDMS, up to two orders of magnitude, by changing the solvent. In these experiments, we use circular 3D channels and characterize the etching rate of the channels using TBAF dissolved in 16 common, organic solvents. Etching of PDMS by TBAF is currently thought to be mediated by the attack of the Si -O bonds of PDMS by the naked fl uoride. [23][24][25] The exact mechanism for the reaction between the naked fl uoride and the Si -O bonds remains unknown. From our current etching experiments, we demonstrate that the wide range of PDMS removal rates depends on two factors: (1) the reactivity of TBAF with Si -O bonds in the solvent, which in turn depends on the polarity of the solvent and (2) the degree of solvent swelling of PDMS.