Rational Design of an Organometallic Glutathione Transferase Inhibitor

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Cysteine cathepsins proteases are enzymes that play essential physiological roles, but their activity is also associated to different aspects of cancer progression and to the development of other diseases. Therefore, cysteine cathepsins are relevant and pr ...

ABCG2 is an ATP-binding cassette transporter that exports a wide range of xenobiotic compounds and has been recognized as a contributing factor for multidrug resistance in cancer cells. Substrate and inhibitor interactions with ABCG2 have been extensively ...

One of the main goals of organometallic chemistry in the last decades was the activation of small molecule in mild reaction conditions. Even though multiple examples of catalytic cycles able to produce fine chemicals from cheap and abundant sources using t ...

Protein-protein interactions (PPIs) are responsible for regulating many biological processes in human bodies. PPIs often have a large binding site and often interact through an alpha helical segment. Therefore, the inhibition of PPIs can be difficult using ...

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing epsilon-N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but ...

Protein-protein interactions (PPIs) play important roles in many diseases and their modulation is an attractive strategy for developing new therapeutics. However, the relatively large and often flat binding surfaces of PPIs makes the development of inhibit ...

For several years, drugs with reactive electrophilic appendages have been developed. These units typically confer prolonged residence time of the drugs on their protein targets, and may assist targeting shallow binding sites and/or improving the drug-prote ...

Macrocycles are an attractive class of molecules due to their good binding properties and yet rather small size that allows, in many cases, crossing membranes to reach intracellular targets. In comparison to classical small molecule drugs, macrocycles are ...

ABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to multidrug resistance of cancer cells. In previously reported structures, the reaction cycle was halted by the absence of substrates or ATP, mutation of catalytic residue ...

Here we provide a personal account of innovation and design principles underpinning a method to interrogate precision electrophile signaling that has come to be known as "REX technologies". This Account is framed in the context of trying to improve methods ...

Most of our understanding of chemistry derives from atomic-level structures obtained with single-crystal X-ray diffraction. Metal centers in X-ray structures of small organometallic or coordination complexes are often extremely well-defined, with errors in ...

Polymorphonuclear neutrophils contain at least four serine endopeptidases, namely neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and NSP4, which contribute to the regulation of infection and of inflammatory processes. In physiological co ...

Ability to faithfully report drug-target interactions constitutes a major critical parameter in preclinical/clinical settings. Yet the assessment of target engagement remains challenging, particularly for promiscuous and/or polypharmacologic ligands. Drawi ...

Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases at the intersection of health and disease due to their involvement in processes such as tissue repair and immunity as well as cancer and inflammation. Because of the high structural conserv ...

Synthetic protein switches are proteins that can be controlled by an external input, and are useful tools to probe protein function. Antibody fragments and antibody mimetics can be selected to bind, activate, or inhibit several diverse protein targets. Nev ...

Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can ...

Tuberculosis (TB), whose etiological agent is Mycobacterium tuberculosis (M. tuberculosis), has plagued humanity since antiquity. Even with chemotherapy available today, TB is the leading cause of death due to an infectious disease. Modern day factors, suc ...

Chiral lactam 2 and three chiral 3-amino alcohols 3-5 have been synthesized and characterized by Sspectroscopic techniques. Regioselective ring opening reaction of chiral styrene oxide by an amine nucle-ophile was confirmed by X-ray diffraction data. Ligan ...

Ions differ in their ability to salt out proteins from solution as expressed in the lyotropic or Hofmeister series of cations and anions. Since its first formulation in 1888, this series has been invoked in a plethora of effects, going beyond the original ...

The therapeutic benefits of the neuraminidase (NA) inhibitor oseltamivir are dampened by the emergence of drug resistance mutations in influenza A virus (IAV). To investigate the mechanistic features that underlie resistance, we developed an approach to qu ...

Rational Design of an Organometallic Glutathione Transferase Inhibitor

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Development of cysteine cathepsin inhibitors combined with cell type-specific delivery for the treatment of B-cell lymphoma and solid tumors

Structural Basis of the Allosteric Inhibition of Human ABCG2 by Nanobodies

Tuning the reactivity of uranium towards small molecules in multimetallic complexes

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Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme

Generating macrocyclic inhibitors of protein-protein interactions

Can Precision Electrophile Signaling Make a Meaningful and Lasting Impression in Drug Design?

Methods for the generation of large combinatorial macrocycle libraries

Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism

An Oculus to Profile and Probe Target Engagement In Vivo: How T-REX Was Born and Its Evolution into G-REX

Picometer Resolution Structure of the Coordination Sphere in the Metal-Binding Site in a Metalloprotein by NMR

Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin

Genie in a bottle: controlled release helps tame natural polypharmacology?

Engineered peptide macrocycles can inhibit matrix metalloproteinases with high selectivity

Allosteric Protein Switches based on Antibody Mimetics

The evolution of multiple active site configurations in a designed enzyme

More Medicines for Tuberculosis: Fuelling Drug Discovery against Mycobacterium tuberculosis

Synthesis and crystal structure of a chiral lactam and three amino alcohols as potential protein tyrosine phosphates 1B inhibitors

Beyond the Hofmeister Series: Ion-Specific Effects on Proteins and Their Biological Functions

A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance