Co-reporter:Pedro M. S. D. Cal;Florian Sieglitz;Fábio M. F. Santos;Cátia Parente Carvalho;Ana Guerreiro;Jean B. Bertoldo;Uwe Pischel;Pedro M. P. Gois;Gonçalo J. L. Bernardes
Chemical Communications 2017 vol. 53(Issue 2) pp:368-371
Publication Date(Web):2016/12/22
DOI:10.1039/C6CC08671C
Fluorophores are indispensable for imaging biological processes. We report the design and synthesis of azide-tagged boronic acid salicylidenehydrazone (BASHY) dyes and their use for site-selective labelling of Annexin V. The Annexin V-BASHY conjugate maintained function and fluorescence as demonstrated by the targeted detection of apoptotic cells.
Co-reporter:Jean B. Bertoldo, Tiago Rodrigues, Lavinia Dunsmore, Francesco A. Aprile, ... Gonçalo J.L. Bernardes
Chem 2017 Volume 3, Issue 4(Volume 3, Issue 4) pp:
Publication Date(Web):12 October 2017
DOI:10.1016/j.chempr.2017.07.009
•Chemical editing•Cys-H2O-Cys bridge•Insights on resistance to oxidative inactivationThe emergence of Mycobacterium tuberculosis (Mtb) resistance is a serious threat to public health. However, the quest for more efficient drugs against Mtb is hampered by the lack of a detailed understanding of Mtb virulence protein effectors. Here, we describe the swift modification of select Cys residues in multi-Cys proteins directly through chemistry. New insights into the biochemistry of emerging bacterial drug targets were obtained. We reveal a water Cys-Cys bridging mechanism that offers an explanation for the known resistance of Mtb protein tyrosine phosphatase A (PtpA) to the oxidative conditions that prevail within an infected host macrophage. This water Cys-Cys bridge motif is also found in the phosphatase SptpA from Staphylococcus aureus, suggesting its potential conserved structural role. The rationalization of the unique features of PtpA, an important target for Mtb drug discovery, could now be used in the design of novel small-molecule modulators.The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains highlights the need to develop more efficacious and potent drugs. However, this goal is dependent on a comprehensive understanding of Mtb virulence protein effectors at the molecular level. Here, we used a post-expression cysteine (Cys)-to-dehydrolanine (Dha) chemical editing strategy to identify a water-mediated motif that modulates accessibility of the protein tyrosine phosphatase A (PtpA) catalytic pocket. Importantly, this water-mediated Cys-Cys non-covalent motif is also present in the phosphatase SptpA from Staphylococcus aureus, which suggests a potentially preserved structural feature among bacterial tyrosine phosphatases. The identification of this structural water provides insight into the known resistance of Mtb PtpA to the oxidative conditions that prevail within an infected host macrophage. This strategy could be applied to extend the understanding of the dynamics and function(s) of proteins in their native state and ultimately aid in the design of small-molecule modulators.Download high-res image (170KB)Download full-size image
Co-reporter:Padma Akkapeddi, Saara-Anne Azizi, Allyson M. Freedy, Pedro M. S. D. Cal, Pedro M. P. Gois and Gonçalo J. L. Bernardes
Chemical Science 2016 vol. 7(Issue 5) pp:2954-2963
Publication Date(Web):12 Feb 2016
DOI:10.1039/C6SC00170J
Systemic chemotherapy, the current standard of care for the treatment of cancer, is rarely curative and is often accompanied by debilitating side effects. Targeted drug delivery stands as an alternative to chemotherapy, with the potential to improve upon its low efficacy and systemic toxicity. Among targeted therapeutic options, antibody–drug conjugates (ADCs) have emerged as the most promising. These conjugates represent a new class of biopharmaceuticals that selectively deliver potent cytotoxic drugs to cancer cells, sparing healthy tissue throughout the body. Despite this promise, early heterogenous ADCs suffered from stability, pharmacokinetic, and efficacy issues that hindered clinical development. Recent advances in antibody engineering, linkers for drug-release, and chemical site-selective antibody conjugation have led to the creation of homogenous ADCs that have proven to be more efficacious than their heterogeneous predecessors both in vitro and in vivo. In this minireview, we focus on and discuss recent advances in chemical site-selective modification strategies for the conjugation of drugs to antibodies and the resulting potential for the development of a new generation of homogenous ADCs.
Co-reporter:Diana Montes-Grajales, Gonçalo J. L. Bernardes, and Jesus Olivero-Verbel
Chemical Research in Toxicology 2016 Volume 29(Issue 2) pp:150
Publication Date(Web):December 23, 2015
DOI:10.1021/acs.chemrestox.5b00342
Humans are exposed to a huge amount of environmental pollutants called endocrine disrupting chemicals (EDCs). These molecules interfere with the homeostasis of the body, usually through mimicking natural hormones leading to activation or blocking of their receptors. Many of these compounds have been associated with a broad range of diseases including the development or increased susceptibility to breast cancer, the most prevalent cancer in women worldwide, according to the World Health Organization. Thus, this article presents a virtual high-throughput screening (vHTS) to evaluate the affinity of proteins related to breast cancer, such as ESR1, ERBB2, PGR, BCRA1, and SHBG, among others, with EDCs from urban sources. A blind docking strategy was employed to screen each protein–ligand pair in triplicate in AutoDock Vina 2.0, using the computed binding affinities as ranking criteria. The three-dimensional structures were previously obtained from EDCs DataBank and Protein Data Bank, prepared and optimized by SYBYL X-2.0. Some of the chemicals that exhibited the best affinity scores for breast cancer proteins in each category were 1,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A derivatives, perfluorooctanesulfonic acid, and benzo(a)pyrene, for catalase, several proteins, sex hormone-binding globulin, and cytochrome P450 1A2, respectively. An experimental validation of this approach was performed with a complex that gave a moderate binding affinity in silico, the sex hormone binding globulin (SHBG), and bisphenol A (BPA) complex. The protein was obtained using DNA recombinant technology and the physical interaction with BPA assessed through spectroscopic techniques. BPA binds on the recombinant SHBG, and this results in an increase of its α helix content. In short, this work shows the potential of several EDCs to bind breast cancer associated proteins as a tool to prioritize compounds to perform in vitro analysis to benefit the regulation or exposure prevention by the general population.
Co-reporter:Omar Boutureira and Gonçalo J. L. Bernardes
Chemical Reviews 2015 Volume 115(Issue 5) pp:2174
Publication Date(Web):February 20, 2015
DOI:10.1021/cr500399p
Co-reporter:Míriam Salvadó, Beatrice Amgarten, Sergio Castillón, Gonçalo J. L. Bernardes, and Omar Boutureira
Organic Letters 2015 Volume 17(Issue 11) pp:2836-2839
Publication Date(Web):May 22, 2015
DOI:10.1021/acs.orglett.5b01259
2-Deoxy-2-fluoroglycosyl iodides are privileged glycosyl donors for the stereoselective preparation of 1-Nu-β-fluorosugars, which are useful reagents for chemical site-selective protein glycosylation. Ready access to such β-fluorosugars enables the mild and efficient construction of well-defined fluoroglycoproteins.
Co-reporter:Beatrice Amgarten, Rakesh Rajan, Nuria Martínez-Sáez, Bruno L. Oliveira, Inês S. Albuquerque, Roger A. Brooks, David G. Reid, Melinda J. Duer and Gonçalo J. L. Bernardes
Chemical Communications 2015 vol. 51(Issue 25) pp:5250-5252
Publication Date(Web):18 Nov 2014
DOI:10.1039/C4CC07974D
We have developed a strategy for selective imaging of collagen in live foetal ovine osteoblasts. Our approach involves the incorporation of an azide-tagged proline in the biosynthesis of collagen followed by labelling using a strain-promoted [3+2] azide–alkyne cycloaddition reaction.
Co-reporter:Inês S. Albuquerque, Hélia F. Jeremias, Miguel Chaves-Ferreira, Dijana Matak-Vinkovic, Omar Boutureira, Carlos C. Romão and Gonçalo J. L. Bernardes
Chemical Communications 2015 vol. 51(Issue 19) pp:3993-3996
Publication Date(Web):30 Jan 2015
DOI:10.1039/C4CC10204E
We report the design and synthesis of an aquacarbonyl Ru(II) dication cis-[Ru(CO)2(H2O)4]2+ reagent for histidine (His)-selective metallation of interleukin (IL)-8 at site 33. The artificial, non-toxic interleukin (IL)-8-RuII(CO)2 metalloprotein retained IL-8-dependent neutrophil chemotactic activity and was shown to spontaneously release CO in live cells.
Co-reporter:Dr. Miguel Chaves-Ferreira;Inês S. Albuquerque;Dr. Dijana Matak-Vinkovic;Dr. Ana C. Coelho;Dr. Sra M. Carvalho;Dr. Lígia M. Saraiva; Carlos C. Romão;Dr. Gonçalo J. L. Bernardes
Angewandte Chemie International Edition 2015 Volume 54( Issue 4) pp:1172-1175
Publication Date(Web):
DOI:10.1002/anie.201409344
Abstract
We demonstrate that RuII(CO)2–protein complexes, formed by the reaction of the hydrolytic decomposition products of [fac-RuCl(κ2-H2NCH2CO2)(CO)3] (CORM-3) with histidine residues exposed on the surface of proteins, spontaneously release CO in aqueous solution, cells, and mice. CO release was detected by mass spectrometry (MS) and confocal microscopy using a CO-responsive turn-on fluorescent probe. These findings support our hypothesis that plasma proteins act as CO carriers after in vivo administration of CORM-3. CO released from a synthetic bovine serum albumin (BSA)–RuII(CO)2 complex leads to downregulation of the cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in cancer cells. Finally, administration of BSA–RuII(CO)2 in mice bearing a colon carcinoma tumor results in enhanced CO accumulation at the tumor. Our data suggest the use of RuII(CO)2–protein complexes as viable alternatives for the safe and spatially controlled delivery of therapeutic CO in vivo.
Co-reporter:Ana Loureiro, Gonçalo J.L. Bernardes, Ulyana Shimanovich, Marisa P. Sárria, Eugénia Nogueira, Ana Preto, Andreia C. Gomes, Artur Cavaco-Paulo
Nanomedicine: Nanotechnology, Biology and Medicine 2015 Volume 11(Issue 5) pp:1077-1083
Publication Date(Web):July 2015
DOI:10.1016/j.nano.2015.02.022
Folic Acid (FA)-tagged protein nanoemulsions were found to be preferentially internalized on B-cell lymphoma cell line (A20 cell line), which, for the first time, is reported to express folate receptor (FR)-alpha. Carbon monoxide releasing molecule-2 (CORM-2) was incorporated in the oil phase of the initial formulation. FA-functionalized nanoemulsions loaded with CORM-2 exhibited a considerable antitumor effect and an increased survival of BALB/c mice bearing subcutaneous A20 lymphoma tumors. The developed nanoemulsions also demonstrated to be well tolerated by these immunocompetent mice. Thus, the results obtained in this study demonstrate that FA-tagged protein nanoemulsions can be successfully used in cancer therapy, with the important ability to delivery drugs intracellularly.From the Clinical EditorIn this research, the authors developed folic acid tagged nanoemulsions containing a carbon monoxide releasing protein molecule for targeted cancer cell treatment. In-vitro and in-vivo experiments showed efficacy against B-cell lymphoma cells. The same nanocarrier platform could be applied to other tumor cells expressing folate receptors on the cell surface.A novel therapeutic approach using folic acid (FA)-tagged protein nanoemulsions, as targeting carrier, and Carbon-Monoxide Releasing Molecule 2 (CORM-2) was described and discussed. FA-tagged protein nanoemulsions loaded with CORM-2, a hydrophobic anti-proliferative drug, induce a strong antitumor effect and increased the survival of mice bearing subcutaneous A20 lymphoma tumors.
Co-reporter:Ulyana Shimanovich, Gonçalo J. L. Bernardes, T. P. J. Knowles and Artur Cavaco-Paulo
Chemical Society Reviews 2014 vol. 43(Issue 5) pp:1361-1371
Publication Date(Web):12 Dec 2013
DOI:10.1039/C3CS60376H
Micro- and nano-scale systems have emerged as important tools for developing clinically useful drug delivery systems. In this tutorial review, we discuss the exploitation of biomacromolecules for this purpose, focusing on proteins, polypeptides, nucleic acids and polysaccharides and mixtures thereof as potential building blocks for novel drug delivery systems. We focus on the mechanisms of formation of micro- and nano-scale protein-based capsules and shells, as well as on the functionalization of such structures for use in targeted delivery of bioactive materials. We summarise existing methods for protein-based capsule synthesis and functionalization and highlight future challenges and opportunities for delivery strategies based on biomacromolecules.
Co-reporter:Dr. Sra García-Gallego;Dr. Gonçalo J. L. Bernardes
Angewandte Chemie International Edition 2014 Volume 53( Issue 37) pp:9712-9721
Publication Date(Web):
DOI:10.1002/anie.201311225
Abstract
The development of carbon-monoxide-releasing molecules (CORMs) as pharmaceutical agents represents an attractive and safer alternative to administration of gaseous CO. Most CORMs developed to date are transition-metal carbonyl complexes. Although such CORMs have showed promising results in the treatment of a number of animal models of disease, they still lack the necessary attributes for clinical development. Described in this Minireview are the methods used for CORM selection, to date, and how new insights into the reactivity of metal-carbonyl complexes in vivo, together with advances in methods for live-cell CO detection, are driving the design and synthesis of new CORMs, CORMs that will enable controlled CO release in vivo in a spatial and temporal manner without affecting oxygen transport by hemoglobin.
Co-reporter:Pedro M. S. D. Cal;Dr. Gonçalo J. L. Bernardes;Dr. Pedro M. P. Gois
Angewandte Chemie International Edition 2014 Volume 53( Issue 40) pp:10585-10587
Publication Date(Web):
DOI:10.1002/anie.201405702
Co-reporter:Dr. Sra García-Gallego;Dr. Gonçalo J. L. Bernardes
Angewandte Chemie 2014 Volume 126( Issue 37) pp:9868-9877
Publication Date(Web):
DOI:10.1002/ange.201311225
Abstract
Die Entwicklung Kohlenmonoxid freisetzender Moleküle (carbon-monoxide-releasing molecules, CORMs) als pharmazeutische Wirkstoffe stellt eine attraktive und sichere Alternative zur Verabreichung von gasförmigem CO dar. Die meisten bisher entwickelten CORMs sind Carbonylkomplexe von Übergangsmetallen. Obgleich derartige CORMs im Tierversuch bei einer Reihe von Krankheiten vielversprechende Resultate gezeitigt haben, fehlen ihnen noch die notwendigen Attribute für eine weitergehende klinische Entwicklung. Hier werden die bis jetzt entwickelten Methoden der CORM-Selektion beschrieben. Weiterhin werden neue Erkenntnisse hinsichtlich der In-vivo-Reaktivität von Metall-Carbonylkomplexen im Zusammenhang mit Methoden für den CO-Nachweis in lebenden Zellen dargelegt. Es wird aufgezeigt, wie diese den Entwurf und die Synthese neuer CORMs vorantreiben.
Co-reporter:Pedro M. S. D. Cal;Dr. Gonçalo J. L. Bernardes;Dr. Pedro M. P. Gois
Angewandte Chemie 2014 Volume 126( Issue 40) pp:10758-10760
Publication Date(Web):
DOI:10.1002/ange.201405702
Co-reporter:Roberto Adamo, Alberto Nilo, Bastien Castagner, Omar Boutureira, Francesco Berti and Gonçalo J. L. Bernardes
Chemical Science 2013 vol. 4(Issue 8) pp:2995-3008
Publication Date(Web):07 May 2013
DOI:10.1039/C3SC50862E
Primary examples in vaccine design have shown good levels of carbohydrate-specific antibody generation when raised using extracted or fully synthetic capsular polysaccharide glycans covalently coupled to a protein carrier. Herein, we cover recent clinical developments of carbohydrate-based vaccines and describe how novel cutting-edge methodology for the total synthesis of oligosaccharides and for the precise placement of carbohydrates at pre-determined sites within a protein may be used to further improve the safety and efficacy of glycovaccines.
Co-reporter:Gonçalo J. L. Bernardes
Chemical Communications 2013 vol. 49(Issue 77) pp:8578-8582
Publication Date(Web):13 Aug 2013
DOI:10.1039/C3CC90259E
A graphical abstract is available for this content
Co-reporter:Gonçalo J. L. Bernardes
Chemical Communications 2013 - vol. 49(Issue 77) pp:NaN8582-8582
Publication Date(Web):2013/08/13
DOI:10.1039/C3CC90259E
A graphical abstract is available for this content
Co-reporter:Pedro M. S. D. Cal, Florian Sieglitz, Fábio M. F. Santos, Cátia Parente Carvalho, Ana Guerreiro, Jean B. Bertoldo, Uwe Pischel, Pedro M. P. Gois and Gonçalo J. L. Bernardes
Chemical Communications 2017 - vol. 53(Issue 2) pp:NaN371-371
Publication Date(Web):2016/11/30
DOI:10.1039/C6CC08671C
Fluorophores are indispensable for imaging biological processes. We report the design and synthesis of azide-tagged boronic acid salicylidenehydrazone (BASHY) dyes and their use for site-selective labelling of Annexin V. The Annexin V-BASHY conjugate maintained function and fluorescence as demonstrated by the targeted detection of apoptotic cells.
Co-reporter:Beatrice Amgarten, Rakesh Rajan, Nuria Martínez-Sáez, Bruno L. Oliveira, Inês S. Albuquerque, Roger A. Brooks, David G. Reid, Melinda J. Duer and Gonçalo J. L. Bernardes
Chemical Communications 2015 - vol. 51(Issue 25) pp:NaN5252-5252
Publication Date(Web):2014/11/18
DOI:10.1039/C4CC07974D
We have developed a strategy for selective imaging of collagen in live foetal ovine osteoblasts. Our approach involves the incorporation of an azide-tagged proline in the biosynthesis of collagen followed by labelling using a strain-promoted [3+2] azide–alkyne cycloaddition reaction.
Co-reporter:Padma Akkapeddi, Saara-Anne Azizi, Allyson M. Freedy, Pedro M. S. D. Cal, Pedro M. P. Gois and Gonçalo J. L. Bernardes
Chemical Science (2010-Present) 2016 - vol. 7(Issue 5) pp:NaN2963-2963
Publication Date(Web):2016/02/12
DOI:10.1039/C6SC00170J
Systemic chemotherapy, the current standard of care for the treatment of cancer, is rarely curative and is often accompanied by debilitating side effects. Targeted drug delivery stands as an alternative to chemotherapy, with the potential to improve upon its low efficacy and systemic toxicity. Among targeted therapeutic options, antibody–drug conjugates (ADCs) have emerged as the most promising. These conjugates represent a new class of biopharmaceuticals that selectively deliver potent cytotoxic drugs to cancer cells, sparing healthy tissue throughout the body. Despite this promise, early heterogenous ADCs suffered from stability, pharmacokinetic, and efficacy issues that hindered clinical development. Recent advances in antibody engineering, linkers for drug-release, and chemical site-selective antibody conjugation have led to the creation of homogenous ADCs that have proven to be more efficacious than their heterogeneous predecessors both in vitro and in vivo. In this minireview, we focus on and discuss recent advances in chemical site-selective modification strategies for the conjugation of drugs to antibodies and the resulting potential for the development of a new generation of homogenous ADCs.
Co-reporter:Roberto Adamo, Alberto Nilo, Bastien Castagner, Omar Boutureira, Francesco Berti and Gonçalo J. L. Bernardes
Chemical Science (2010-Present) 2013 - vol. 4(Issue 8) pp:NaN3008-3008
Publication Date(Web):2013/05/07
DOI:10.1039/C3SC50862E
Primary examples in vaccine design have shown good levels of carbohydrate-specific antibody generation when raised using extracted or fully synthetic capsular polysaccharide glycans covalently coupled to a protein carrier. Herein, we cover recent clinical developments of carbohydrate-based vaccines and describe how novel cutting-edge methodology for the total synthesis of oligosaccharides and for the precise placement of carbohydrates at pre-determined sites within a protein may be used to further improve the safety and efficacy of glycovaccines.
Co-reporter:Inês S. Albuquerque, Hélia F. Jeremias, Miguel Chaves-Ferreira, Dijana Matak-Vinkovic, Omar Boutureira, Carlos C. Romão and Gonçalo J. L. Bernardes
Chemical Communications 2015 - vol. 51(Issue 19) pp:NaN3996-3996
Publication Date(Web):2015/01/30
DOI:10.1039/C4CC10204E
We report the design and synthesis of an aquacarbonyl Ru(II) dication cis-[Ru(CO)2(H2O)4]2+ reagent for histidine (His)-selective metallation of interleukin (IL)-8 at site 33. The artificial, non-toxic interleukin (IL)-8-RuII(CO)2 metalloprotein retained IL-8-dependent neutrophil chemotactic activity and was shown to spontaneously release CO in live cells.
Co-reporter:Tiago Rodrigues, Florian Sieglitz and Gonçalo J. L. Bernardes
Chemical Society Reviews 2016 - vol. 45(Issue 22) pp:NaN6137-6137
Publication Date(Web):2016/02/18
DOI:10.1039/C5CS00916B
Treatment of cancer is a significant challenge in clinical medicine, and its research is a top priority in chemical biology and drug discovery. Consequently, there is an urgent need for identifying innovative chemotypes capable of modulating unexploited drug targets. The transient receptor potential (TRPs) channels persist scarcely explored as targets, despite intervening in a plethora of pathophysiological events in numerous diseases, including cancer. Both agonists and antagonists have proven capable of evoking phenotype changes leading to either cell death or reduced cell migration. Among these, natural products entail biologically pre-validated and privileged architectures for TRP recognition. Furthermore, several natural products have significantly contributed to our current knowledge on TRP biology. In this Tutorial Review we focus on selected natural products, e.g. capsaicinoids, cannabinoids and terpenes, by highlighting challenges and opportunities in their use as starting points for designing natural product-inspired TRP channel modulators. Importantly, the de-orphanization of natural products as TRP channel ligands may leverage their exploration as viable strategy for developing anticancer therapies. Finally, we foresee that TRP channels may be explored for the selective pharmacodelivery of cytotoxic payloads to diseased tissues, providing an innovative platform in chemical biology and molecular medicine.
Co-reporter:Ulyana Shimanovich, Gonçalo J. L. Bernardes, T. P. J. Knowles and Artur Cavaco-Paulo
Chemical Society Reviews 2014 - vol. 43(Issue 5) pp:NaN1371-1371
Publication Date(Web):2013/12/12
DOI:10.1039/C3CS60376H
Micro- and nano-scale systems have emerged as important tools for developing clinically useful drug delivery systems. In this tutorial review, we discuss the exploitation of biomacromolecules for this purpose, focusing on proteins, polypeptides, nucleic acids and polysaccharides and mixtures thereof as potential building blocks for novel drug delivery systems. We focus on the mechanisms of formation of micro- and nano-scale protein-based capsules and shells, as well as on the functionalization of such structures for use in targeted delivery of bioactive materials. We summarise existing methods for protein-based capsule synthesis and functionalization and highlight future challenges and opportunities for delivery strategies based on biomacromolecules.
![1H-BENZ[E]INDOL-5-OL, 3-ACETYL-1-(CHLOROMETHYL)-2,3-DIHYDRO-, (1S)-](http://img.cochemist.com/ccimg/550400/550356-55-3.png)
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![L-Tyrosine, N-[(1,1-dimethylethoxy)carbonyl]-O-ethenyl-, methyl ester](http://img.cochemist.com/ccimg/389900/389867-33-8.png)
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![Spiro[1H-isoindole-1,9'-[9H]xanthen]-3(2H)-one, 2-(2-aminoethyl)-3',6'-bis(diethylamino)-](/data/chemimg/106200/950846-89-6.png)
![Spiro[1H-isoindole-1,9'-[9H]xanthen]-3(2H)-one, 2-(2-aminoethyl)-3',6'-bis(diethylamino)-](/data/chemimg/106200/950846-89-6_b.png)
