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

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


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”

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


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

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


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.