Boronic Acid for the Traceless Delivery of Proteins into Cells

Andersen, Kristen A.; Smith, Thomas P.; Lomax, Jo E.; Raines, Ronald T.

doi:10.1021/acschembio.5b00966

Cited by 52 publications

(66 citation statements)

References 55 publications

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“…This is an important conclusion not only for the benzoxaborole drugs currently being developed, but also for other biomedical applications of these molecules, in which they being used as sugar-targeting agents for the internalization of proteins in cells [7,39]. Moreover, it means that the formulation of benzoxaborole-based molecules by grafting onto calcium phosphates like hydroxyapatite will most probably lead to a fast (burst) release, which can nevertheless be subsequently tuned through the preparation of apatite/biopolymer composites using a strategy that is described in our recent work on PLLA-LDH formulations of benzoxaboroles [12].…”

Section: Discussionmentioning

confidence: 99%

Adsorption of benzoxaboroles on hydroxyapatite phases

Pizzoccaro¹,

Nikel²,

Sene³

et al. 2016

Acta Biomaterialia

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Benzoxaboroles are a family of molecules that are finding an increasing number of applications in the biomedical field, particularly as a “privileged scaffold” for the design of new drugs. Here, for the first time, we determine the interaction of these molecules with hydroxyapatites, in view of establishing (i) how benzoxaborole drugs may adsorb onto biological apatites, as this could impact on their bioavailability, and (ii) how apatite-based materials can be used for their formulation. Studies on the adsorption of the benzoxaborole motif (C7H7BO2, referred to as BBzx) on two different apatite phases were thus performed, using a ceramic hydroxyapatite (HAceram) and a nanocrystalline hydroxyapatite (HAnano), the latter having a structure and composition more similar to the one found in bone mineral. In both cases, the grafting kinetics and mechanism were studied, and demonstration of the surface attachment of the benzoxaborole under the form of a tetrahedral benzoxaborolate anion was established using 11B solid state NMR (including 11B-31P correlation experiments). Irrespective of the apatite used, the grafting density of the benzoxaborolates was found to be low, and more generally, these anions demonstrated a poor affinity for apatite surfaces, notably in comparison with other anions commonly found in biological media, such as carboxylates and (organo)phosphates. The study was then extended to the adsorption of a molecule with antimicrobial and antifungal properties (3-piperazine-bis(benzoxaborole)), showing, on a more general perspective, how hydroxyapatites can be used for the development of novel formulations of benzoxaborole drugs.

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Section: Discussionmentioning

confidence: 99%

Adsorption of benzoxaboroles on hydroxyapatite phases

Pizzoccaro¹,

Nikel²,

Sene³

et al. 2016

Acta Biomaterialia

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“…[53] Verglichen mit den üblichen Zeitskalen von Biokonjugationen und Labeling-Anwendungen ist diese Nebenreaktion unter In-vivo-Bedingungen allerdings generell langsam. [57,58] Sie zeigten, dass die zelluläre Befçrderung des Modellproteins RNase Adurch die Benzoxaborol-konjugierte RNase Abegünstigt wird. In diesem Zusammenhang berichteten Schultz und Mitarbeiter von der zentrendirigierten nichtnatürlichen Aminosäuremutagenese von Boronsäuren in GFP, [55] [43][44][45][46][47] In den meisten Fällen bedient man sich hierbei der Boronatbildung mit biologischen Polyolen oder bestimmten Saccharideinheiten auf Glykoproteinen.…”

Section: Boronsäuren Als Bioorthogonale Sondenunclassified

“…[54] Andererseits kann die Reaktivitäta uch in bioorthogonalen Reaktionen eingesetzt werden (Schema 4D). [58] Zelluläre Esterasen sind in menschlichen Zellen reichlich vorhanden. [56] So setzten Raines und Mitarbeiter beispielsweise kürzlich die Hemiboronsäure Benzoxaborol ein, um Boronataddukte mit der Glykokalyx auf der Zellmembran auszubilden (Schema 5).…”

Section: Boronsäuren Als Bioorthogonale Sondenunclassified

Boronsäuren als bioorthogonale Sonden für zentrenselektives Protein‐Labeling

Akgun¹,

Hall²

2018

Angewandte Chemie

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In den vergangenen zwei Jahrzehnten hat sich die bioorthogonale Chemie zu einem beliebten Hilfsmittel entwickelt, um zentrenselektive Modifikationen an Proteinen zu erzielen. Dennoch sind nur einige wenige bioorthogonale Reaktionen bekannt, die zudem Limitierungen aufweisen können, wie etwa geringe Reaktionsgeschwindigkeiten, die Verwendung instabiler oder zytotoxischer Reagenzien und das Auftreten von Nebenreaktionen. Folglich besteht ein großes Interesse an der Erweiterung der Methodik in der bioorthogonalen Chemie. In diesem Zusammenhang wurden kürzlich Boronsäuren in den Bereich der bioorthogonalen Chemie eingeführt, welche in drei verschiedenen Strategien zum Einsatz kommen: 1) Bildung eines Boronsäureesters zwischen der Boronsäure und einem 1,2‐cis‐Diol; 2) Bildung eines Iminoboronates zwischen 2‐Acetyl‐/Formyl‐Arylboronsäure und Hydrazin‐/Hydroxylamin‐/Semicarbazid‐Derivaten; 3) Verwendung einer Boronsäure als Transfergruppe in einer Suzuki‐Miyaura‐Kreuzkupplung oder einer anderen Reaktion, in deren Verlauf die Boronylgruppe das Intermediat verlässt. In diesem Aufsatz fassen wir die Fortschritte der Anwendung von Boronsäuren in der bioorthogonalen Chemie zusammen, welche das zentrenspezifische Labeling von Proteinen ermöglicht, und vergleichen diese Methoden mit den gängigsten bioorthogonalen Reaktionen.

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“…33,34 Boronic acids (including the FDA-approved drug Bortezomib 35 ) are well known as serine/threonine protease inhibitors, 36,39 anti-microbial and anti-cancer agents, 40,41 and delivery vehicles. 42–45 Boronic acid-based fluorogenic probes have been developed for sensing both saccharides 46 and reactive oxygen species, 47,48 as well as for molecular recognition 49 and protein conjugation. 50,51 These applications arise from the ability of boronic acids to form a covalent bond with a Lewis base that is reversible under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation

et al. 2017

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Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure–function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.

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Boronic Acid for the Traceless Delivery of Proteins into Cells

Cited by 52 publications

References 55 publications

Adsorption of benzoxaboroles on hydroxyapatite phases

Adsorption of benzoxaboroles on hydroxyapatite phases

Boronsäuren als bioorthogonale Sonden für zentrenselektives Protein‐Labeling

Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation

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