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Bioconjugate Chemistry

Andrew W L Kinman, Rebecca R Pompano
Enzymatic antibody fragmentation has been well studied for various hosts and isotypes, but fragmentation patterns also vary unpredictably by clone, and optimizing Fab or F(ab')2 production by trial and error consumes large quantities of antibodies. Here, we report a systematic strategy for optimizing functional F(ab')2 production via pepsin digestion from small quantities of IgG. We tested three key parameters that affect fragmentation: pH, enzyme concentration (% pepsin w/w), and reaction time, and found that pH had the greatest impact on fragmentation yield and efficiency...
January 16, 2019: Bioconjugate Chemistry
Nitin Patil, John Karas, Bradley J Turner, Fazel Shabanpoor
Antisense oligonucleotides (ASO)-based drugs are emerging with great potential as therapeutic compounds for diseases with unmet medical needs. However, for ASOs to be effective as clinical entities, they should reach their intracellular RNA and DNA targets at pharmacologically relevant concentrations. Over the past decades various covalently attached delivery vehicles have been utilised for intracellular delivery of ASOs. One such approach is the use of biocompatible cell-penetrating peptides (CPPs) covalently conjugated to ASOs...
January 15, 2019: Bioconjugate Chemistry
Alexander R Grimm, Daniel F Sauer, Tayebeh Mirzaei Garakani, Kristin Rübsam, Tino Polen, Mehdi D Davari, Felix Jakob, Johannes Schiffels, Jun Okuda, Ulrich Schwaneberg
Adhesion promoting peptides have been reported to enable efficient enzyme immobilization on various material surfaces. Here we report the first immobilization of a synthetic Grubbs-Hoveyda (GH) type catalyst on two different materials (silica and polypropylene). To this end, the GH catalyst was coupled to an engineered (F16C) variant of the adhesion promoting peptide LCI through thiol-maleimide "click" reaction. Immobilization was performed in an oriented manner through the adhesion promoting peptide by simple incubation with the materials in water and subsequent washing with water and tetrahydrofuran...
January 15, 2019: Bioconjugate Chemistry
Marco D Torelli, Ashlyn G Rickard, Marina Backer, Daria S Filonov, Nicholas Nunn, Alexander V Kinev, Joseph M Backer, Gregory M Palmer, Olga A Shenderova
The increased expression of vascular endothelial growth factor (VEGF) and its receptors is associated with angiogenesis in a growing tumor, presenting potential targets for tumor-selective imaging by way of targeted tracers. Though fluorescent tracers are used for targeted in vivo imaging, the lack of photostability and biocompatibility of many current fluorophores hinder their use in several applications involving long-term, continuous imaging. To address these problems, fluorescent nanodiamonds (FNDs), which exhibit infinite photostability and excellent biocompatibility, were explored as fluorophores in tracers for targeting VEGF receptors in growing tumors...
January 11, 2019: Bioconjugate Chemistry
Jeongdeok Seo, Jonghwan Lee, Chaebin Lee, Soo Kyung Bae, Kun Na
Non-polymer, pH-sensitive carbon dots (pSCDs) was developed to overcome the disadvantage of pH-sensitive polymers such as inevitable synthesis, wide distribution of molecular weight, uncontrolled loading and release rate of drug, and toxicity by biodegradation. The pSCDs were synthesized by one spot synthesis for 3 min using citric acid (CA) and 1-(3-aminopropyl) imidazole (API). Imidazole groups were present on pSCD surfaces and facilitated DOX loading via hydrophobic interactions (loading efficiency: 78.55%)...
January 11, 2019: Bioconjugate Chemistry
Yipeng Du, Hao Hu, Xiaoxia Pei, Kang Du, Taotao Wei
Malonyl-CoA is one of the key metabolic intermediates in fatty acid metabolism as well as a key player in protein posttranslational modifications. Detection of malonyl-CoA in live cells is challenging because of the lack of effective measuring tools. Here we developed a genetically-encoded biosensor, FapR-NLuc, by combining a malonyl-CoA responsive bacterial transcriptional factor, FapR, with an engineered luciferase, NanoLuciferase (NLuc). FapR-NLuc specifically responds to malonyl-CoA and enables the rapid detection of malonyl-CoA at the micromolar level...
January 10, 2019: Bioconjugate Chemistry
Diksha Haksar, Eyleen de Poel, Linda H C Quarles van Ufford, Sumati Bhatia, Rainer Haag, Jeffrey M Beekman, Roland J Pieters
Cholera is a potentially fatal bacterial infection that affects a large number of people in the developing countries. It is caused by the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. The toxin comprises of a toxic A-subunit and a pentameric B-subunit that binds to the intestinal cell surface. Several monovalent and multivalent inhibitors of the toxin have been synthesized but are too complicated and expensive for practical use in developing countries. Meta-nitrophenyl α-galactoside (MNPG) is a known promising ligand for CT and here mono- and multivalent compounds based on MNPG were synthesized...
January 10, 2019: Bioconjugate Chemistry
Andrea Patrizia Falanga, Vincenzo Cerullo, Maria Marzano, Sara Feola, Giorgia Oliviero, Gennaro Piccialli, Nicola Borbone
The B-cell lymphoma 2 (Bcl-2) gene encodes for an antiapoptotic protein associated with the onset of many human tumors. Several oligonucleotides (ONs) and ON analogues are under study as potential tools to counteract the Bcl-2 expression. Among these are Peptide Nucleic Acids (PNAs). The absence of charges on PNA backbones allows the formation of PNA/DNA complexes provided with higher stability than the corresponding natural DNA/DNA counterparts. To date, the use of PNAs in antigene or antisense strategies is strongly limited by their inability to cross efficiently the cellular membranes...
January 8, 2019: Bioconjugate Chemistry
Meltem Göksel
Trametes versicolor can degrade barks as a source for carbon necessity. Therefore it secretes lignin peroxidase, mangan peroxidase and laccase. The laccase enzyme was produced high yield at pH and glucose concentration 5 and 10 gL-1, respectively. In optimized medium, the enzyme activity was between 200-250 UL-1 when inducer was absent. It was seen that the activity reached 400 UL-1 when phenol used as an inducer. The molecular weight of purified laccase was found 80 kDa with SDS-PAGE and kinetic constant Km and Vmax values for ABTS were determined 3...
January 8, 2019: Bioconjugate Chemistry
Joseph Lau, Orit Jacobson, Gang Niu, Kuo-Shyan Lin, François Bénard, Xiaoyuan Chen
Radioligand therapy (RLT) relies on the use of pharmacophores to selectively deliver ionization energy to cancers to exert its tumoricidal effects. Cancer cells that are not directly targeted by a radioconjugate remain susceptible to RLT because of the crossfire effect. This is significant given the inter- and intra-heterogeneity of tumors. In recent years, reversible albumin binders have been used as simple 'add-ons' for radiopharmaceuticals to modify pharmacokinetics and to enhance therapeutic efficacy. In this review, we discuss recent advances in albumin binder platforms used in RLT, with an emphasis on 4-(p-iodophenyl)butyric acid and Evans blue derivatives...
January 8, 2019: Bioconjugate Chemistry
Anselm Fabian Lowell Schneider, Antoine L D Wallabregue, Luise Franz, Christian P R Hackenberger
The delivery of entire functional proteins into living cells is a long-sought goal in science. Cyclic cell-penetrating peptides (cCPPs) have proven themselves to be potent delivery vehicles to carry proteins upon conjugation into the cytosol of living cells with im-mediate bioavailability via a non-endosomal uptake pathway. With this strategy, we pursue the cytosolic delivery of mCherry, a medi-um-sized fluorescent protein. Afterwards, we achieve subcellular delivery of mCherry to different intracellular loci by genetic fusion of targeting peptides to the protein sequence...
January 8, 2019: Bioconjugate Chemistry
Matteo Di Giosia, Federica Nicolini, Lucia Ferrazzano, Alice Soldà, Francesco Valle, Andrea Cantelli, Tainah Dorina Marforio, Andrea Bottoni, Francesco Zerbetto, Marco Montalti, Stefania Rapino, Alessandra Tolomelli, Matteo Calvaresi
The lack of solubility in water and the formation of aggregates hamper many opportunities of technological ex-ploitation of C60. Here different peptides were designed and synthesized with the aim of dispersing monomo-lecularly C60 in water. Phenylalanines were used as recognizing moieties, able to interact with C60 through π-π stacking, while a varying number of glycines were used as spacers, to connect the two terminal phenylalanines. The best performance in the dispersion of C60 was obtained with the FGGGF peptidic nanotweezer at a pH of 12...
January 7, 2019: Bioconjugate Chemistry
Jacques Pliquett, Adrien Dubois, Cindy Racoeur, Nesrine Mabrouk, Souheila Amor, Robin Lescure, Ali Bettaieb, Bertrand Collin, Claire Bernhard, Franck Denat, Pierre-Simon Bellaye, Catherine Paul, Ewen Bodio, Christine Goze
A new family of water-soluble and bioconjugatable aza-BODIPY fluorophores was designed and synthesized using a boron- functionalization strategy. These dissymmetric bis-ammonium aza-BODIPY dyes present optimal properties for a fluorescent probe, i.e. they are highly water-soluble, very stable in physiological medium, they do not aggregate in PBS, possess high quantum yield and finally they can be easily bioconjugated to antibodies. Preliminary in vitro and in vivo studies were per-formed for one of these fluorophores to image PD-L1 (Programmed Death-Ligand 1), highlighting the high potential of these new probes for future in vivo optical imaging studies...
January 7, 2019: Bioconjugate Chemistry
Kundansingh Pardeshi, T Anand Kumar, Govindan Ravikumar, Grace Kaul, Manjulika Shukla, Sidharth Chopra, Harinath Chakrapani
Fluoroquinolones (FQs) are among the front-line antibiotics used to treat severe infections caused by Gram-negative bacteria. However, recently due to toxicity concerns, their use has been severely restrict-ed. Hence, efforts to direct delivery of this antibiotic specifically to bacteria/site of infection are under-way. Here, we report a strategy that uses a bacterial enzyme for activation of a prodrug to generate the active antibiotic. The ciprofloxacin-latent fluorophore conjugate 1, which is designed as a substrate for nitroreductase (NTR), a bacterial enzyme was synthesized...
January 7, 2019: Bioconjugate Chemistry
Maaz S Ahmed, Christopher Blake Rodell, Maarten Hulsmans, Rainer H Kohler, Aaron Aguirre, Matthias Nahrendorf, Ralph Weissleder
Amiodarone is an effective anti-arrhythmic drug used to treat and prevent different types of cardiac arrhythmias. However, amiodarone can have considerable side effects resulting from accumulation in off-target tissues. Cardiac macrophages are highly prevalent tissue-resident immune cells with importance in homeostatic functions, including immune response and modulation of cardiac conduction. We hypothesized that amiodarone could be more efficiently delivered to the heart via cardiac macrophages, an important step toward reducing overall dose and off-target tissue accumulation...
January 7, 2019: Bioconjugate Chemistry
Rachel M Lieser, Wilfred Chen, Millicent O Sullivan
Proteins are ideal candidates for disease treatment because of their high specificity and potency. Despite this potential, delivery of proteins remains a significant challenge due to the intrinsic size, charge, and stability of proteins. Attempts to overcome these challenges have most commonly relied on direct conjugation of polymers and peptides to proteins via reactive groups on naturally occurring residues. While such approaches have shown some success, they allow limited control of the spacing and number of moieties coupled to proteins, which can hinder bioactivity and delivery capabilities of the therapeutic...
January 7, 2019: Bioconjugate Chemistry
Serena Fortunato, Chiara Lenzi, Carlotta Granchi, Valentina Citi, Alma Martelli, Vincenzo Calderone, Sebastiano Di Pietro, Giovanni Signore, Valeria Di Bussolo, Filippo Minutolo
H2 S-donors are currently emerging as promising therapeutic agents in a wide variety of pathologies, including tumors. Cancer cells are characterized by an enhanced uptake of sugars, such as glucose. Therefore, novel glycoconjugated H2 S-donors were synthesized, so that high concentrations of H2 S can be selectively achieved therein. Dithiolethione- or isothiocyanate-portions were selected for their well-known H2 S-releasing properties in the presence of biological substrates. A synthetic procedure employing trichloroacetimidate glycosyl donors was applied to produce, in a stereoselective fashion, C1-glycoconjugates, whereas C6-glycoconjugates were obtained by a Mitsunobu-based transformation...
January 4, 2019: Bioconjugate Chemistry
Andreas Ritler, Michal Shoshan, Xavier Deupi, Patrick Wilhelm, Roger Schibli, Helma Wennemers, Martin Behe
Derivatized minigastrin analogues are a promising class of candidates to target the cholecystokinin receptor subtype 2 (CCK2R), which is overexpressed on cancer cells of various neuroendocrine tumors (NETs). The pentaglutamic acid sequence of minigastrin influences its biological properties. In particular, it plays a crucial role in the kidney reuptake mechanism. However, the importance for the binding affinity and interaction of this region with the receptor on a molecular level remains unclear. In order to elucidate its structure-activity relationship with the CCK2R, we replaced this sequence with various linkers differing in their amount of anionic charges, structural characteristics, and flexibility...
January 4, 2019: Bioconjugate Chemistry
Sebastien Benizri, Arnaud Gissot, Andrew Martin, Brune Vialet, Philippe Barthelemy, Mark W Grinstaff
Oligonucleotide-based agents have the potential to treat or cure almost any disease, and are one of the key therapeutic drug classes of the future. Bioconjugated oligonucleotides, a subset of this class, are emerging from basic research and being successfully translated to the clinic. In this review, we first briefly describe two approaches for inhibiting specific genes using oligonucleotides - antisense DNA (ASO) and RNA interference (RNAi) - followed by a discussion on delivery to cells. We then summarize and analyze recent developments in bioconjugated oligonucleotides including those possessing GalNAc, cell penetrating peptides, α-tocopherol, aptamers, antibodies, cholesterol, squalene, fatty acids, or nucleolipids...
January 4, 2019: Bioconjugate Chemistry
Satoshi Kishimoto, Yuichi Nakashimada, Riri Yokota, Takaaki Hatanaka, Motoyasu Adachi, Yuji Ito
Artificially modified IgG molecules are increasingly utilized in industrial and clinical applications. In the present study, the method of chemical conjugation by affinity peptide (CCAP) for site-specific chemical modification has been developed by using a peptide that bound with high affinity to human IgG-Fc. This method enabled a rapid modification of a specific res-idue (Lys248 on Fc) in a one-step reaction under mild condition to form a stable amide bond between the peptide and Fc. The monovalent peptide-IgG conjugate not only maintained complete antigen binding but also bound to Fc receptors (FcRn, FcRγI, and FcRγIIIa), indicating that it is a suitable conjugate form that can be further developed into highly func-tional antibody therapeutics...
January 4, 2019: Bioconjugate Chemistry
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