scholarly journals Amine‐Tagged Fragmented Ligand Installation for Covalent Modification of MOF‐74

2021 ◽  
Author(s):  
Jaewoong Lim ◽  
Seonghwan Lee ◽  
Hyeonbin Ha ◽  
Junmo Seong ◽  
Seok Jeong ◽  
...  
Keyword(s):  
Covalent Modification

scholarly journals An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jerod L. Ptacin ◽  
Carolina E. Caffaro ◽  
Lina Ma ◽  
Kristine M. San Jose Gall ◽  
Hans R. Aerni ◽  
...  
Keyword(s):  
Nk Cells ◽  
Large Scale ◽  
Tumor Therapy ◽  
Covalent Modification ◽  
Synthetic Dna ◽  
Expansion Characteristic ◽  
Synthetic Organisms ◽  
Dose Dependent ◽  
Receptor Beta

AbstractThe implementation of applied engineering principles to create synthetic biological systems promises to revolutionize medicine, but application of fundamentally redesigned organisms has thus far not impacted practical drug development. Here we utilize an engineered microbial organism with a six-letter semi-synthetic DNA code to generate a library of site-specific, click chemistry compatible amino acid substitutions in the human cytokine IL-2. Targeted covalent modification of IL-2 variants with PEG polymers and screening identifies compounds with distinct IL-2 receptor specificities and improved pharmacological properties. One variant, termed THOR-707, selectively engages the IL-2 receptor beta/gamma complex without engagement of the IL-2 receptor alpha. In mice, administration of THOR-707 results in large-scale activation and amplification of CD8+ T cells and NK cells, without Treg expansion characteristic of IL-2. In syngeneic B16-F10 tumor-bearing mice, THOR-707 enhances drug accumulation in the tumor tissue, stimulates tumor-infiltrating CD8+ T and NK cells, and leads to a dose-dependent reduction of tumor growth. These results support further characterization of the immune modulatory, anti-tumor properties of THOR-707 and represent a fundamental advance in the application of synthetic biology to medicine, leveraging engineered semi-synthetic organisms as cellular factories to facilitate discovery and production of differentiated classes of chemically modified biologics.

scholarly journals A New Method for Dispersing Pristine Carbon Nanotubes Using Regularly Arranged S-Layer Proteins

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1346
Author(s):  
Andreas Breitwieser ◽  
Uwe B. Sleytr ◽  
Dietmar Pum
Keyword(s):  
Carbon Nanotubes ◽  
Covalent Modification ◽  
Silica Layer ◽  
Medical Sciences ◽  
Lysinibacillus Sphaericus ◽  
Wide Range ◽  
Catalytic Sites ◽  
Multi Walled Carbon Nanotubes ◽  
Pristine Mwnts ◽  
Walled Carbon Nanotubes

Homogeneous and stable dispersions of functionalized carbon nanotubes (CNTs) in aqueous solutions are imperative for a wide range of applications, especially in life and medical sciences. Various covalent and non-covalent approaches were published to separate the bundles into individual tubes. In this context, this work demonstrates the non-covalent modification and dispersion of pristine multi-walled carbon nanotubes (MWNTs) using two S-layer proteins, namely, SbpA from Lysinibacillus sphaericus CCM2177 and SbsB from Geobacillus stearothermophilus PV72/p2. Both the S-layer proteins coated the MWNTs completely. Furthermore, it was shown that SbpA can form caps at the ends of MWNTs. Reassembly experiments involving a mixture of both S-layer proteins in the same solution showed that the MWNTs were primarily coated with SbsB, whereas SbpA formed self-assembled layers. The dispersibility of the pristine nanotubes coated with SbpA was determined by zeta potential measurements (−24.4 +/− 0.6 mV, pH = 7). Finally, the SbpA-coated MWNTs were silicified with tetramethoxysilane (TMOS) using a mild biogenic approach. As expected, the thickness of the silica layer could be controlled by the reaction time and was 6.3 +/− 1.25 nm after 5 min and 25.0 +/− 5.9 nm after 15 min. Since S-layer proteins have already demonstrated their capability to bind (bio)molecules in dense packing or to act as catalytic sites in biomineralization processes, the successful coating of pristine MWNTs has great potential in the development of new materials, such as biosensor architectures.

scholarly journals PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Parp Inhibitors ◽  
Covalent Modification ◽  
Activation Mechanism ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Complementary Role ◽  
Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

scholarly journals Influence of Dopamine on Fluorescent Advanced Glycation End Products Formation Using Drosophila melanogaster

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 453
Author(s):  
Ana Filošević Vujnović ◽  
Katarina Jović ◽  
Emanuel Pištan ◽  
Rozi Andretić Waldowski
Keyword(s):  
Drosophila Melanogaster ◽  
Advanced Glycation End Products ◽  
Model Organism ◽  
Covalent Modification ◽  
Advanced Glycation ◽  
Biomarkers Of Aging ◽  
Glycation End Products ◽  
End Products

Non-enzymatic glycation and covalent modification of proteins leads to Advanced Glycation End products (AGEs). AGEs are biomarkers of aging and neurodegenerative disease, and can be induced by impaired neuronal signaling. The objective of this study was to investigate if manipulation of dopamine (DA) in vitro using the model protein, bovine serum albumin (BSA), and in vivo using the model organism Drosophila melanogaster, influences fluorescent AGEs (fAGEs) formation as an indicator of dopamine-induced oxidation events. DA inhibited fAGEs-BSA synthesis in vitro, suggesting an anti-oxidative effect, which was not observed when flies were fed DA. Feeding flies cocaine and methamphetamine led to increased fAGEs formation. Mutants lacking the dopaminergic transporter or the D1-type showed further elevation of fAGEs accumulation, indicating that the long-term perturbation in DA function leads to higher production of fAGEs. To confirm that DA has oxidative properties in vivo, we fed flies antioxidant quercetin (QUE) together with methamphetamine. QUE significantly decreased methamphetamine-induced fAGEs formation suggesting that the perturbation of DA function in vivo leads to increased oxidation. These findings present arguments for the use of fAGEs as a biomarker of DA-associated neurodegenerative changes and for assessment of antioxidant interventions such as QUE treatment.

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