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  1. Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we per-formed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003–2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003–2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2. 
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  2. • The structure-based energy calculations were applied to determine the effects of disease-causing kinesin missense mutations on protein stability and protein-protein interaction. • The mutations associated with Intellectual Disability can decrease the protein stability of KIF1A motor domain. • Hereditary Spastic Paraplegia mutations located in kinesin-tubulin complex interface can destabilize the binding infinity of KIF5A-tubulin complex. 
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  3. Abstract

    trans‐Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or in vivo experiments. Described is a new class of TCOs, “a‐TCOs”, prepared in high yield by stereocontrolled 1,2‐additions of nucleophiles to trans‐cyclooct‐4‐enone, which itself was prepared on a large scale in two steps from 1,5‐cyclooctadiene. Computational transition‐state models rationalize the diastereoselectivity of 1,2‐additions to deliver a‐TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans‐oxocene analogue. Illustrating the favorable physicochemical properties of a‐TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell‐permeable through intracellular Diels–Alder chemistry and to wash out more rapidly than other TCOs.

     
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  4. Abstract

    trans‐Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or in vivo experiments. Described is a new class of TCOs, “a‐TCOs”, prepared in high yield by stereocontrolled 1,2‐additions of nucleophiles to trans‐cyclooct‐4‐enone, which itself was prepared on a large scale in two steps from 1,5‐cyclooctadiene. Computational transition‐state models rationalize the diastereoselectivity of 1,2‐additions to deliver a‐TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans‐oxocene analogue. Illustrating the favorable physicochemical properties of a‐TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell‐permeable through intracellular Diels–Alder chemistry and to wash out more rapidly than other TCOs.

     
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  5. Abstract

    Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here is a general, one‐pot method for converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells.

     
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  6. Abstract

    Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here is a general, one‐pot method for converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells.

     
    more » « less