Electronic Effects of Bidentate ,-Ligands on the Elementary Steps of Au(I)/Au(III) Reactions Relevant to Cross-Coupling Chemistry.

Oxidant-free Au(I)/Au(III)-catalyzed cross-coupling has been recently enabled by the use of bidentate ,-ligands. To further develop these ,-ligands, computational studies were performed to understand their effects on the oxidative addition of aryl iodide electrophiles with Au(I). Using this mechanistic understanding, six new electron-rich ,-ligands were synthesized.

A Glucose-Responsive Glucagon-Micelle for the Prevention of Hypoglycemia.

While glucose-responsive insulin delivery systems are in widespread clinical use to treat insulin insufficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains understudied. A self-regulated glucagon release material is highly desired to mitigate the potential risks of severe insulin-induced hypoglycemia. Here, we describe a glucose-responsive polymeric nanosystem with glucagon covalently grafted to the end-group.

Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction.

Controlling rates and reversibilities of elimination reactions of hydroxybenzylammoniums by tuning dearomatization energies.

Hydroxybenzylammonium compounds can undergo a reversible 1,4- or 1,6-elimination to afford quinone methide intermediates after release of the amine. These molecules are useful for the reversible conjugation of payloads to amines. We hypothesized that aromaticity could be used to alter the rate of reversibility as a distinct thermodynamic driving force.

Organometallic Oxidative Addition Complexes for -Arylation of Free Cysteines.

Development of bioconjugation strategies to efficiently modify biomolecules is of key importance for fundamental and translational scientific studies. Cysteine -arylation is an approach which is becoming more popular due to generally rapid kinetics and high chemoselectivity, as well as the strong covalently bonded -aryl linkage created in these processes. Organometallic approaches to cysteine -arylation have been explored that feature many advantages compared to their more traditional organic counterparts.

Enzyme-Polymer Conjugates with Photocleavable Linkers for Control Over Protein Activity.

Reversible conjugation of polymers to proteins is important for a variety of applications, for example to control protein activity. Light is often employed as an external trigger to allow for spatio and temporal control over release of a payload. In this report, we demonstrate preparation of photocleavable poly(polyethylene glycol) acrylate)-lysozyme (pPEGA-Lys) conjugates -nitrobenzyl linkages.

Uniform trehalose nanogels for glucagon stabilization.

Glucagon is a peptide hormone that acts receptor-mediated signaling predominantly in the liver to raise glucose levels by hepatic glycogen breakdown or conversion of noncarbohydrate, 3 carbon precursors to glucose by gluconeogenesis. Glucagon is administered to reverse severe hypoglycemia, a clinical complication associated with type 1 diabetes. However, due to low stability and solubility at neutral pH, there are limitations in the current formulations of glucagon.

Ultrafast Au(III)-Mediated Arylation of Cysteine.

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, the developed organometallic Au(III) bioconjugation reagents enable selective labeling of Cys moieties down to picomolar concentrations and allow for the rapid construction of complex heterostructures from peptides, proteins, and oligonucleotides. This work showcases how organometallic chemistry can be interfaced with biomolecules and lead to a range of reactivities that are largely unmatched by classical organic chemistry tools.

In situ analysis of osmolyte mechanisms of proteome thermal stabilization.

Organisms use organic molecules called osmolytes to adapt to environmental conditions. In vitro studies indicate that osmolytes thermally stabilize proteins, but mechanisms are controversial, and systematic studies within the cellular milieu are lacking. We analyzed Escherichia coli and human protein thermal stabilization by osmolytes in situ and across the proteome.

Caffeine and Cationic Copolymers with Antimicrobial Properties.

One of the primary global health concerns is the increase in antimicrobial resistance. Polymer chemistry enables the preparation of macromolecules with hydrophobic and cationic side chains that kill bacteria by destabilizing their membranes. In the current study, macromolecules are prepared by radical copolymerization of caffeine methacrylate as the hydrophobic monomer and cationic- or zwitterionic-methacrylate monomers.

Noncovalent Enzyme Nanogels via a Photocleavable Linkage.

Enzyme nanogels (ENGs) offer a convenient method to protect therapeutic proteins from in vivo stressors. Current methodologies to prepare ENGs rely on either covalent modification of surface residues or the noncovalent assembly of monomers at the protein surface. In this study, we report a new method for the preparation of noncovalent ENGs that utilizes a heterobifunctional, photocleavable monomer as a hybrid approach.

Poly(trehalose methacrylate) as an Excipient for Insulin Stabilization: Mechanism and Safety.

Insulin, the oldest U.S. Food and Drug Administration (FDA)-approved recombinant protein and a World Health Organization (WHO) essential medicine for treating diabetes globally, faces challenges due to its storage instability.

Organometallic -arylation Reagents for Rapid PEGylation of Biomolecules.

Bioconjugation techniques for biomolecule-polymer conjugation are numerous; however, slow kinetics and steric challenges generally necessitate excess reagents or long reaction times. Organometallic transformations are known to circumvent these issues; yet, harsh reaction conditions, incompatibility in aqueous media, and substrate promiscuity often limit their use in a biological context. The work reported herein demonstrates a facile and benign organometallic Au(III) -arylation approach that enables the synthesis of poly(ethylene glycol) monomethyl ether (mPEG)-protein conjugates with high efficiency.

Safety and Biodistribution Profile of Poly(styrenyl acetal trehalose) and Its Granulocyte Colony Stimulating Factor Conjugate.

Poly(styrenyl acetal trehalose) (pSAT), composed of trehalose side chains linked to a polystyrene backbone via acetals, stabilizes a variety of proteins and enzymes against fluctuations in temperature. A promising application of pSAT is conjugation of the polymer to therapeutic proteins to reduce renal clearance. To explore this possibility, the safety of the polymer was first studied.

Effect of Poly(trehalose methacrylate) Molecular Weight and Concentration on the Stability and Viscosity of Insulin.

Instability to storage and shipping conditions and injection administration remain major challenges in treating chronic conditions with biopharmaceuticals. Herein, formulations of poly(trehalose methacrylate) (pTrMA) were successfully optimized to stabilize insulin without appreciably increasing viscosity. Polymers were synthesized (2,400 - 29,200 Da), and added to insulin at different concentrations.

Diazido macrocyclic sulfates as a platform for the synthesis of sequence-defined polymers for antibody drug conjugates.

To improve the efficacy of antibody drug conjugates (ADCs), there has been significant focus on increasing the drug-to-antibody ratio (DAR) in order to deliver more payload. However, due to the hydrophobicity of many cytotoxics, highly-loaded conjugates often have lower physicochemical stability and poorer pharmacokinetic outcomes, requiring the development of new hydrophilic linkers. Herein, we report a platform for the preparation of functional, sequence-defined polymers for conjugation to antibodies.

Synthesis of Disulfide-Bridging Trehalose Polymers for Antibody and Fab Conjugation Using a Bis-Sulfone ATRP Initiator.

Antibodies and antigen binding fragments (FABs) are widely used as therapeutics and conjugated polymers can enhance the properties of these important biomolecules. However, limitations to the selectivity and stability of current conjugation methodologies can inhibit the exploration of new antibody-polymer conjugates. Herein, we describe a new strategy for the synthesis of these conjugates that forms a stable thioether bond and can be directly incorporated into an atom transfer radical polymerization (ATRP) initiator.