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Article ; Online: Bioorthogonal Decaging Reactions for Targeted Drug Activation

Sarah Davies / Benjamin J. Stenton / Gonçalo J. L. Bernardes

CHIMIA, Vol 72, Iss

2018 Volume 11

Abstract: Bioorthogonal decaging reactions are highly selective transformations which involve the cleavage of a protecting group from a molecule of interest. Decaging reactions can be classified into subgroups depending on the nature of the trigger; they can be ... ...

Abstract	Bioorthogonal decaging reactions are highly selective transformations which involve the cleavage of a protecting group from a molecule of interest. Decaging reactions can be classified into subgroups depending on the nature of the trigger; they can be photo-, metal- or small molecule-triggered. Due to their highly selective and biocompatible nature, they can be carried out in living systems as they do not interfere with any endogenous processes. This gain-of-function allows controlled activation of proteins and release of fluorophores and drugs in vivo. Although there are many examples of fluorophore/protein release, this review focuses on the application of bioorthogonal decaging reactions for targeted drug activation. One strategy for targeted drug delivery is tissue-selective activation of prodrugs and antibody–drug conjugates (ADCs). Bioorthogonal decaging provides a highly selective, controllable method for activating prodrugs and ADCs, reducing toxicity due to the off-target drug release that occurs in endogenous activation strategies. Here we focus on the development of bifunctional linkers that enable studies of bioorthogonal chemistry for activation of ADCs.
Keywords	Antibody–drug conjugates ; Bifunctional linkers ; Bioorthogonal decaging ; Targeted drug delivery ; Chemistry ; QD1-999
Subject code	540
Language	German
Publishing date	2018-11-01T00:00:00Z
Publisher	Swiss Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combating small-molecule aggregation with machine learning

Kuan Lee / Ann Yang / Yen-Chu Lin / Daniel Reker / Gonçalo J.L. Bernardes / Tiago Rodrigues

Cell Reports Physical Science, Vol 2, Iss 9, Pp 100573- (2021)

2021

Abstract: Summary: Biological screens are plagued by false-positive hits resulting from aggregation. Methods to triage small colloidally aggregating molecules (SCAMs) are in high demand. Herein, we disclose a neural network to flag such entities. Our data ... ...

Abstract	Summary: Biological screens are plagued by false-positive hits resulting from aggregation. Methods to triage small colloidally aggregating molecules (SCAMs) are in high demand. Herein, we disclose a neural network to flag such entities. Our data demonstrate the utility of machine learning for predicting SCAMs, achieving 80% of correct predictions in an out-of-sample evaluation. The tool is competitive with a panel of expert chemists, who correctly predict 61% ± 7% of the same molecules in a Turing-like test. Our computational routine provides insight into features governing aggregation that had remained hidden to expert intuition. Further, we quantify that up to 15%–20% of ligands in publicly available chemogenomic databases have high potential to aggregate at a typical screening concentration (30 μM), imposing caution in systems biology and drug design programs. Our approach provides a means to augment human intuition and mitigate attrition and a pathway to accelerate future molecular medicine.
Keywords	chemical biology ; false positive hits ; small molecule triage ; machine intelligence ; drug discovery ; Physics ; QC1-999
Subject code	006
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural insights into TRPV2 activation by small molecules

Ruth A. Pumroy / Anna D. Protopopova / Tabea C. Fricke / Iris U. Lange / Ferdinand M. Haug / Phuong T. Nguyen / Pamela N. Gallo / Bárbara B. Sousa / Gonçalo J. L. Bernardes / Vladimir Yarov-Yarovoy / Andreas Leffler / Vera Y. Moiseenkova-Bell

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: A non-selective calcium channel transient receptor potential vanilloid 2 (TRPV2) is a potential drug target. Here, the authors employ cryo-electron microscopy, in silico docking, and electrophysiology to identify a binding site for an activator 2- ... ...

Abstract	A non-selective calcium channel transient receptor potential vanilloid 2 (TRPV2) is a potential drug target. Here, the authors employ cryo-electron microscopy, in silico docking, and electrophysiology to identify a binding site for an activator 2-aminoethoxydiphenyl borate (2-APB) in this channel.
Keywords	Science ; Q
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Discovery of 2,4-dimethoxypyridines as novel autophagy inhibitors

Robke, Lucas / Daniel J. Foley / Gonçalo J.L. Bernardes / Herbert Waldmann / Luca Laraia / Peter Schröder / Tiago Rodrigues

Tetrahedron. 2018,

2018

Abstract: Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen ...

Abstract	Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen for autophagy inhibitors, which led to the discovery of a dimethoxypyridine-based class of autophagy inhibitors, which derive from previously reported, natural product-inspired MAP4K4 inhibitors. Comprehensive structure-activity relationship studies led to a potent compound, and biological validation experiments indicated that the mode of action was upstream or independent of mTOR.
Keywords	autophagy ; chemical reactions ; mechanism of action ; organic compounds ; phenotype ; structure-activity relationships
Language	English
Size	p. .
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	204285-x
ISSN	1464-5416 ; 0040-4020 ; 0563-2064
ISSN (online)	1464-5416
ISSN	0040-4020 ; 0563-2064
DOI	10.1016/j.tet.2018.07.021
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

Mafalda M. A. Pereira / Inês Mahú / Elsa Seixas / Noelia Martinéz-Sánchez / Nadiya Kubasova / Roksana M Pirzgalska / Paul Cohen / Marcelo O Dietrich / Miguel López / Gonçalo J. L. Bernardes / Ana I. Domingos

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 11

Abstract: Diphtheria toxin selectively kills cells engineered to express the diphtheria toxin receptor (DTR). Here the authors report a PEGylated version of diphtheria toxin that does not enter the brain, allowing for ablation of only peripheral cells when using ... ...

Abstract	Diphtheria toxin selectively kills cells engineered to express the diphtheria toxin receptor (DTR). Here the authors report a PEGylated version of diphtheria toxin that does not enter the brain, allowing for ablation of only peripheral cells when using Cre lines that drive DTR expression in both the periphery and in the brain.
Keywords	Science ; Q
Language	English
Publishing date	2017-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Mafalda M. A. Pereira / Inês Mahú / Elsa Seixas / Noelia Martinéz-Sánchez / Nadiya Kubasova / Roksana M. Pirzgalska / Paul Cohen / Marcelo O. Dietrich / Miguel López / Gonçalo J. L. Bernardes / Ana I. Domingos

Nature Communications, Vol 8, Iss 1, Pp 1-

Corrigendum: A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

2017 Volume 1

Abstract: Nature Communications 8: Article number: 14967 (2017); Published 3 April 2017; Updated 17 May 2017 The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: [***Human Frontiers Science ... ...

Abstract	Nature Communications 8: Article number: 14967 (2017); Published 3 April 2017; Updated 17 May 2017 The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: [*Human Frontiers Science Program (HFSP) funds the labs of A.I.D. and P.C. *].
Keywords	Science ; Q
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Norbornene probes for the study of cysteine oxidation

Alcock, Lisa J / Kyle D. Farrell / Mawey T. Akol / Gregory H. Jones / Matthew M. Tierney / Holger B. Kramer / Tara L. Pukala / Gonçalo J.L. Bernardes / Michael V. Perkins / Justin M. Chalker

Tetrahedron. 2018 Mar. 22, v. 74, no. 12

2018

Abstract: Cysteine residues on proteins can react with cellular oxidants such as hydrogen peroxide. While this process is important for scavenging excess reactive oxygen species, the products of this oxidation may also mediate cell signalling. To understand the ... ...

Abstract	Cysteine residues on proteins can react with cellular oxidants such as hydrogen peroxide. While this process is important for scavenging excess reactive oxygen species, the products of this oxidation may also mediate cell signalling. To understand the role of cysteine oxidation in biology, selective probes are required to detect and quantify its occurrence. Cysteine oxidation products such as sulfenic acids are sometimes unstable and therefore short-lived. If such cysteine derivatives are to be analysed, rapid reaction with the probe is required. Here we introduce norbornene derivatives as probes for cysteine oxidation, and demonstrate their ability to trap sulfenic acids. The synthesis of norbornene derivatives containing alkyne or biotin affinity tags are also reported to facilitate the use of these probes in chemical biology and proteomics.
Keywords	acids ; alkynes ; biotin ; cell communication ; chemical structure ; cysteine ; hydrogen peroxide ; oxidants ; oxidation ; proteins ; proteomics
Language	English
Dates of publication	2018-0322
Size	p. 1220-1228.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	204285-x
ISSN	1464-5416 ; 0040-4020 ; 0563-2064
ISSN (online)	1464-5416
ISSN	0040-4020 ; 0563-2064
DOI	10.1016/j.tet.2017.11.011
Database	NAL-Catalogue (AGRICOLA)

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Article: Chemoselective Installation of Amine Bonds on Proteins through Aza-Michael Ligation

Freedy, Allyson M / Ana Guerreiro / André A. Neves / Bangwen Xie / Francisco Corzana / Gonçalo J. L. Bernardes / Gonzalo Jiménez-Osés / Karl Nicholls / Kevin M. Brindle / Maria J. Matos / Omar Boutureira / Padma Akkapeddi / Tiago Rodrigues / Víctor J. Somovilla

Journal of the American Chemical Society. 2017 Dec. 20, v. 139, no. 50

2017

Abstract: Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemo- and regioselectivity as well as result in non-native linkages that may suffer from ... ...

Abstract	Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemo- and regioselectivity as well as result in non-native linkages that may suffer from instability in vivo and adversely affect the protein’s structure and function. We describe here the reaction of N-nucleophiles with the amino acid dehydroalanine (Dha) in a protein context. When Dha is chemically installed in proteins, the addition of a wide-range N-nucleophiles enables the rapid formation of amine linkages (secondary and tertiary) in a chemoselective manner under mild, biocompatible conditions. These new linkages are stable at a wide range of pH values (pH 2.8 to 12.8), under reducing conditions (biological thiols such as glutathione) and in human plasma. This method is demonstrated for three proteins and is shown to be fully compatible with disulfide bridges, as evidenced by the selective modification of recombinant albumin that displays 17 structurally relevant disulfides. The practicability and utility of our approach is further demonstrated by the construction of a chemically modified C2A domain of Synaptotagmin-I protein that retains its ability to preferentially bind to apoptotic cells at a level comparable to the native protein. Importantly, the method was useful for building a homogeneous antibody-drug conjugate with a precise drug-to-antibody ratio of 2. The kinase inhibitor crizotinib was directly conjugated to Dha through its piperidine motif, and its antibody-mediated intracellular delivery results in 10-fold improvement of its cancer cell-killing efficacy. The simplicity and exquisite site-selectivity of the aza-Michael ligation described herein allows the construction of stable secondary and tertiary amine-linked protein conjugates without affecting the structure and function of biologically relevant proteins.
Keywords	albumins ; amino acids ; apoptosis ; chemoselectivity ; disulfide bonds ; enzyme inhibitors ; glutathione ; humans ; neoplasms ; pH ; piperidines ; regioselectivity ; sulfides ; therapeutics ; thiols
Language	English
Dates of publication	2017-1220
Size	p. 18365-18375.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.7b10702
Database	NAL-Catalogue (AGRICOLA)

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Article: Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage

Compañón, Ismael / Ana Guerreiro / Vincenzo Mangini / Jorge Castro-López / Margarita Escudero-Casao / Alberto Avenoza / Jesús H. Busto / Sergio Castillón / Jesús Jiménez-Barbero / Juan L. Asensio / Gonzalo Jiménez-Osés / Omar Boutureira / Jesús M. Peregrina / Ramón Hurtado-Guerrero / Roberto Fiammengo / Gonçalo J. L. Bernardes / Francisco Corzana

Journal of the American Chemical Society. 2019 Feb. 06, v. 141, no. 9

2019

Abstract: GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α-O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti- ... ...

Abstract	GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α-O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate–peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors.
Keywords	adjuvants ; antibodies ; antigens ; antiserum ; biopsy ; cancer vaccines ; glycopeptides ; glycosidic linkages ; humoral immunity ; mice ; models ; mucins ; nanogold ; neoplasm cells ; neoplasms ; patients ; receptors ; selenium ; sulfur
Language	English
Dates of publication	2019-0206
Size	p. 4063-4072.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.8b13503
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents

Barbara Bernardim / Pedro M.S.D. Cal / Maria J. Matos / Bruno L. Oliveira / Nuria Martínez-Sáez / Inês S. Albuquerque / Elizabeth Perkins / Francisco Corzana / Antonio C.B. Burtoloso / Gonzalo Jiménez-Osés / Gonçalo J. L. Bernardes

Nature Communications, Vol 7, Iss 1, Pp 1-

2016 Volume 9

Abstract: Current cysteine bioconjugation strategies for protein-drug conjugates synthesis often yield heterogeneous and poorly stable products. Here, the authors use carbonylacrylic derivatives to selectively modify cysteine residues and synthesize biologically ... ...

Abstract	Current cysteine bioconjugation strategies for protein-drug conjugates synthesis often yield heterogeneous and poorly stable products. Here, the authors use carbonylacrylic derivatives to selectively modify cysteine residues and synthesize biologically functional antibody conjugates highly stable in plasma.
Keywords	Science ; Q
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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