Category Archives: Israel Journal of Chemistry

From Immunogenic Peptides to Intrinsically Disordered Proteins

Posted on 11 May 2023 by nH. Jane Dyson, nPeter E. Wrightn

Abstract

It is hard to evaluate the role of individual mentors in the genesis of important ideas. In the case of our realization that proteins do not have to be stably folded to be functional, the influence of Richard Lerner and our collaborative work in the 1980s on the conformations of immunogenic peptides provided a base level of thinking about the nature of polypeptides in water solutions that led us to formulate and develop our ideas on the importance of intrinsic disorder in proteins. This review describes how the insights gained into the behavior of peptides led directly to the realization that proteins were not only capable of being functional while disordered, but also that disorder provided a distinct functional advantage in many important cellular processes.

Richard Lerner’s Bioinspiration: Biomolecular Visualization and Modeling at Scripps Research

Posted on 9 May 2023 by nArthur J. Olson, nMichel F. Sanner, nDavid S. Goodsell, nStefano Forlin

Abstract

In thinking back on Richard Lerner's impact on our lab's trajectory at Scripps Research, we see his fingerprints on all the efforts we have undertaken over the last 40 years. Immunology and virology have been a continuing driving focus in our software development and application within the Molecular Graphics Lab (now the Center for Computational Structural Biology – CCSB), spurred on by the marriage of chemistry with biology that Richard enabled at Scripps. Many of our earliest and continuing computational docking targets have been focused on HIV with collaborations with Chi-Huey Wong and Barry Sharpless. Along with subsequent computational work with Jeff Kelly, Reza Ghadiri, Udi Keinan and Ben Cravatt we have been able to sustain continuous efforts in developing and applying docking and other computational technologies to structural chemistry problems. In this remembrance, we give our reflections of Richard Lerner's character, vision, and his inspiration in our scientific lives and in the environment that he created at Scripps Research.

Adaptive Encapsulation of 1,ω‐Amino‐Acids within the “Pyrene Box”

Posted on 8 May 2023 by

Abstract

Pyrene boxes, self-assembled from 1,3,5,8-pyrene-tetrasulfonate anions, PTS⁴⁻ and Guanidinium G⁺ , amino-guanidinium AG⁺ and hydrated alkali counter cations have been used for the encapsulation of 1,ω-amino-acids of variable lengths. The NMR spectroscopy illustrates that these systems are stable in aqueous solution and encapsulation process involves dynamic or fixed guest molecules within Pyrene box, depending of the nature of the counter-cations. The amide bond coupling between the amino-guanidinium AG⁺ and encapsulated 1,ω-amino-acid guests occur in water in the absence of coupling catalysts. The variable co-encapsulation of the guests via multivalent stabilizing interactions shed light that chemical selection can be obtained from mixtures of 1,ω-amino-acids. Our study involving a comprehensive screening of 18 co-crystal structures help to understand the in-situ fixation of 1,ω-amino-acid guests and their accurate determination of unconventional structures under confinement.

Exploring Membrane‐tethering Technology for Proteins as a Versatile Tool for Uncovering Novel Disease Targets and Advancing Biotherapeutic Development

Posted on 5 May 2023 by

Abstract

Membrane-tethering technology for proteins (MTFP) is a promising approach for the development of therapeutic agents that display bioactive proteins, such as antibodies and cytokines, on the cell surface, resulting in the induction of autocrine signalling. In this review article, we provide a comprehensive overview of the MTFP, including its basic principles, selection of agonist antibodies and peptides, and the identification of novel functions of natural cytokines. Furthermore, we discuss the potential of increasing the therapeutic efficacy of existing treatments by engineering active proteins to the cell and extracellular vesicle surfaces. We suggest that the MTFP has the potential to maximize efficiency in drug discovery by identifying proteins with regulatory functions and engineering existing treatments. Our review highlights the importance of MTFP in basic research and translational research, and its potential to apply the development of biotherapeutics.

Water‐Soluble Aryl‐ and Super Aryl‐Extended Calix[4]pyrroles

Posted on 3 May 2023 by nGemma Aragay, nPablo Ballestern

Abstract

The study of molecular recognition processes in water using biomimetic synthetic receptors provides valuable information for understanding more complex biological processes. In the last decade, our group focused on the use of aryl-extended calix[4]pyrrole (AE−C[4]P) scaffolds for the binding of small polar molecules in water. The cone conformation of tetra-α isomers of aryl-extended calix[4]pyrroles defines a deep hydrophobic cavity with an open end and functionalized with converging hydrogen-bond donor groups in its closed end. In this sense, AE−C[4]Ps can be considered as simple biomimetic analogs of enzyme binding sites. In this account, we describe the synthetic strategies used for the preparation of water-soluble AE- and super aryl-extended (SAE−) C[4]Ps. We review and rationalize the results of their molecular recognition studies in water using pyridyl-N-oxide derivatives and a series of small and neutral polar molecules as guests and comment on their applications as supramolecular and sequestering protective groups.

Probing the Internalization and Efficacy of Antibody‐Drug Conjugate via Site‐Specific Fc‐Glycan Labelling of a Homogeneous Antibody Targeting SSEA‐4 Bearing Tumors

Posted on 22 April 2023 by

Abstract

Antibody drug conjugates (ADC) are an emerging class of pharmaceuticals consisting of cytotoxic agents covalently attached to an antibody designed to target a specific cancer cell surface molecule followed by internalization and intracellular release of payload to exhibit its anticancer activity. Targeted delivery of cytotoxic payload to a variety of specific cells has been demonstrated to have significant enhancement in clinical efficacy and dramatic reduction in off-target toxicity. Site-specific conjugation of payload to the antibody is highly desirable for development of ADC with well-defined antibody-to-drug ratio, enhanced internalization, reduced toxicity, improved stability, desired pharmacological profile and optimal therapeutic index. Here, we reported a site-specific conjugation strategy for evaluation of antibody internalization and efficacy of ADC designed to target SSEA4 on solid tumors. This strategy stems from the azido-fucose tag of a homogeneous antibody Fc-glycan generated via in vitro glycoengineering approach for site-specific conjugation and optimization of antibody-drug ratio to exhibit optimal efficacy. The ADC consisting of a chimeric anti-SSEA4 antibody chMC813-70, conjugated to the antineoplastic agent monomethyl auristatin E via both cleavable and non-cleavable linkers showed excellent cytotoxicity profile towards SSEA4-bearing cancer cells. A clear distinction in cytotoxicity was observed among cancer cells with different SSEA4 expression levels.

Heat‐Up Process: Road to Synthesizing Monodisperse Nanoparticles

Posted on 18 April 2023 by

Abstract

Large-scale synthesis of monodisperse nanoparticles is highly desirable for practical applications of nanoparticles in various fields of emerging technology. Among colloidal synthetic routes of monodisperse nanoparticles, heat-up process, which involves a gradual heating of precursor solution in a batch reactor, has received utmost interest after its successful size-controlled synthesis of various kinds of nanoparticles. In this essay, we discuss the fundamental research regarding the synthesis of monodisperse nanoparticles and describe how researchers developed the heat-up process. The mechanistic insights into this synthetic method and the discovery of size-dependent properties of monodisperse nanoparticles are also presented. We further emphasize its great impacts on utilizing monodisperse nanoparticles synthesized via the heat-up process for biomedical technology, energy conversion and storage devices, as well as electronic and optoelectronic devices.

Crystal Structures of Diaryl Hydrazone and Sulfone Stabilizers in Complex with an Amyloidogenic Light Chain Reveal an Alternate Ligand‐Binding Cavity

Posted on 12 April 2023 by nNicholas L. Yan, nIan A. Wilson, nJeffery W. Kellyn

Abstract

Stabilization of amyloidogenic immunoglobulin light chains (LCs) by binding of small molecule “kinetic stabilizers” is under development as a novel treatment for light chain amyloidosis. From a high-throughput screen, we previously identified 16 full-length (FL) LC stabilizers from five distinct chemotypes. We then obtained structural biological information on two classes of hits, coumarins and hydantoins, revealing that both chemotypes bind to a pocket at the V_L−V_L interface of the FL LC dimer. Here, we report crystal structures of three screening hits from two other chemotypes, diaryl hydrazones and sulfones, in complex with an amyloidogenic FL LC. While two of these hits bind to the previously identified pocket, one diaryl hydrazone binds to a different pocket bisected by the C₂ symmetry axis of the dimer. These data further expand on the FL LC stabilizer-binding surface that could be used in design of more potent FL LC aggregation inhibitors.

Anodic Fluorination, Methoxylation, Acetoxylation, and Cyanation of Heteroatom Organic Compounds Using Boron‐Doped Diamond, GC, and Pt Electrodes

Posted on 24 March 2023 by nHideyuki Nojima, nTakashi Shimoda, nShinsuke Inagi, nToshio Fuchigamin

Abstract

Various anodic substitution reactions such as fluorination, methoxylation, acetoxylation, and cyanation of heteroatom compounds containing a sulfur or nitrogen atom were comparatively studied using boron-doped diamond (BDD), Pt, and glassy carbon (GC) anodes. It was found that BDD anode is highly effective for these anodic substitution reactions similarly to Pt anode although both BDD and GC electrodes are carbon-based materials.

ZIF‐8‐Derived Dual Metal (Fe, Ni)‐Nitrogen‐Doped Porous Carbon for Superior ORR Performance in Universal Acid‐Base Properties Solutions

Posted on 1 February 2023 by

Abstract

Fe-N/C catalysts have currently comparable oxygen reduction reaction (ORR) activity to Pt/C catalysts, which are up for consideration as the most promising non-precious metal material for research. In spite of this, its development and application are limited by the Fenton effect and insufficient stability. Herein, we have fabricated a FeNi-nitrogen-doped porous carbon (FeNi-NPC) catalyst using solvent thermal method, made from the bimetallic (Fe, Ni)-doped ZIF-8. A soft template of glucose was used to control the pore structure and active specific surface area of the catalyst. With the benefit of the electronic effect of the bimetal, FeNi-NPC catalysts exhibit superior ORR activity and stability to Pt/C catalysts in both acidic (E _1/2=0.8672 V) and alkaline (E _1/2=0.8663 V) conditions. FeNi-NPC demonstrated peak power densities in proton exchange membrane fuel cells (PEMFC) of up to 865 mW cm⁻², which exceeds the currently reported M-N/C catalysts. The work presented here will lead to the design of efficient ORR electrocatalysts in PEMFC devices.