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Article ; Online: Proteolysis targeting chimeras in antiviral research.

Desantis, Jenny / Goracci, Laura

Future medicinal chemistry

2022 Volume 14, Issue 7, Page(s) 459–462

MeSH term(s)	Antiviral Agents/pharmacology ; Proteolysis ; Ubiquitination
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2022-02-08
Publishing country	England
Document type	Editorial
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2022-0005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis.

Eleuteri, Michela / Desantis, Jenny / Cruciani, Gabriele / Germani, Raimondo / Goracci, Laura

Organic & biomolecular chemistry

2024 Volume 22, Issue 17, Page(s) 3477–3489

Abstract: Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities. Despite the advances made so far, the structural ... ...

Abstract	Selective degradation of disease-causing proteins using proteolysis targeting chimeras (PROTACs) has gained great attention, thanks to its several advantages over traditional therapeutic modalities. Despite the advances made so far, the structural chemical complexity of PROTACs poses challenges in their synthetic approaches. PROTACs are typically prepared through a convergent approach, first synthesizing two fragments separately (target protein and E3 ligase ligands) and then coupling them to produce a fully assembled PROTAC. The amidation reaction represents the most common coupling exploited in PROTACs synthesis. Unfortunately, the overall isolated yields of such synthetic procedures are usually low due to one or more purification steps to obtain the final PROTAC with acceptable purity. In this work, we focused our attention on the optimization of the final amidation step for the synthesis of an anti-SARS-CoV-2 PROTAC by investigating different amidation coupling reagents and a range of alternative solvents, including ionic liquids (ILs). Among the ILs screened, [OMIM][ClO
MeSH term(s)	Proteolysis ; Ionic Liquids/chemistry ; Ionic Liquids/chemical synthesis ; Ubiquitin-Protein Ligases/metabolism ; SARS-CoV-2 ; Amides/chemistry ; Amides/chemical synthesis ; Humans ; Ligands ; Molecular Structure ; Antiviral Agents/chemistry ; Antiviral Agents/chemical synthesis ; Antiviral Agents/pharmacology ; Proteolysis Targeting Chimera
Chemical Substances	Ionic Liquids ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Amides ; Ligands ; Antiviral Agents ; Proteolysis Targeting Chimera
Language	English
Publishing date	2024-05-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/d4ob00304g
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib.

Bonciarelli, Stefano / Desantis, Jenny / Cerquiglini, Simone / Goracci, Laura

ACS omega

2023 Volume 8, Issue 7, Page(s) 7005–7016

Abstract: Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). ...

Abstract	Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC-MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC-MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c07815
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Article ; Online: VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in

Castellani, Beatrice / Eleuteri, Michela / Di Bona, Stefano / Cruciani, Gabriele / Desantis, Jenny / Goracci, Laura

Journal of medicinal chemistry

2023 Volume 66, Issue 18, Page(s) 13148–13171

Abstract: PROteolysis TArgeting Chimeras (PROTACs) are tripartite molecules consisting of a linker connecting a ligand for a protein of interest to an E3 ligase recruiter, whose rationale relies on proteasome-based protein degradation. PROTACs have expanded as a ... ...

Abstract	PROteolysis TArgeting Chimeras (PROTACs) are tripartite molecules consisting of a linker connecting a ligand for a protein of interest to an E3 ligase recruiter, whose rationale relies on proteasome-based protein degradation. PROTACs have expanded as a therapeutic strategy to open new avenues for unmet medical needs. Leveraging our expertise, we undertook a series of
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01144
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Article ; Online: Analysis of Phosphatidylinositol Modifications by Reactive Nitrogen Species Using LC-MS: Coming to Grips with Their Nitroxidative Susceptibility.

Bonciarelli, Stefano / Neves, Bruna / Domingues, Pedro / Melo, Tânia / Goracci, Laura / Domingues, Maria Rosário

Journal of the American Society for Mass Spectrometry

2023 Volume 34, Issue 7, Page(s) 1372–1382

Abstract: Phosphatidylinositols (PIs) are complex lipids that play a key role in cell signaling. Like other phospholipids, they are esterified with unsaturated fatty acyl residues (FAs), making them susceptible to modification by reactive oxygen and nitrogen ... ...

Abstract	Phosphatidylinositols (PIs) are complex lipids that play a key role in cell signaling. Like other phospholipids, they are esterified with unsaturated fatty acyl residues (FAs), making them susceptible to modification by reactive oxygen and nitrogen species (RNS). Recent studies using mass spectrometry (MS)-based lipidomics approaches have revealed that lipid nitration results in a plethora of structurally and chemically modified lipids (epilipids), including nitrated and nitroxidized derivatives of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, and cardiolipins. However, there is a notable lack of knowledge regarding the characterization of RNS-modified PI derivatives. In this study, we used C18 high-resolution liquid chromatography-tandem MS approaches to describe the fragmentation signature of nitrated and nitroxidized PIs, bearing different fatty acyl chains. Using this approach and accurate mass measurements, we were able to identify nitro- PI derivatives, dinitro- and nitrohydroxy- derivatives for a few PI species. The data showed the typical neutral loss of nitrous acid (HNO
MeSH term(s)	Reactive Nitrogen Species ; Chromatography, Liquid ; Phosphatidylinositols ; Tandem Mass Spectrometry/methods ; Phospholipids ; Nitrates/chemistry
Chemical Substances	Reactive Nitrogen Species ; Phosphatidylinositols ; Phospholipids ; Nitrates
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1073671-2
ISSN	1879-1123 ; 1044-0305
ISSN (online)	1879-1123
ISSN	1044-0305
DOI	10.1021/jasms.3c00057
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Zs.A 4618: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Wireless over-ear headphones: A new source of allergic contact dermatitis to isothiazolinones.

Caroppo, Elena Sofia / Stingeni, Luca / Goracci, Laura / Moretti, Simone / Marietti, Rossella / Bianchi, Leonardo / Tramontana, Marta / Hansel, Katharina

Contact dermatitis

2024 Volume 90, Issue 6, Page(s) 621–625

MeSH term(s)	Dermatitis, Allergic Contact/etiology ; Dermatitis, Allergic Contact/diagnosis ; Humans ; Thiazoles/adverse effects ; Patch Tests ; Female ; Male
Chemical Substances	Thiazoles ; 2-methyl-4-isothiazolin-3-one (229D0E1QFA) ; 5-chloro-2-methyl-4-isothiazolin-3-one (DEL7T5QRPN)
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article ; Case Reports
ZDB-ID	193121-0
ISSN	1600-0536 ; 0105-1873
ISSN (online)	1600-0536
ISSN	0105-1873
DOI	10.1111/cod.14528
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Article ; Online: Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity.

Desantis, Jenny / Bazzacco, Alessandro / Eleuteri, Michela / Tuci, Sara / Bianconi, Elisa / Macchiarulo, Antonio / Mercorelli, Beatrice / Loregian, Arianna / Goracci, Laura

European journal of medicinal chemistry

2024 Volume 268, Page(s) 116202

Abstract: To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related to oncology, immune disorders, and neurodegenerative diseases. On the ... ...

Abstract	To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related to oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in the field of antiviral drug discovery is still in its infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum antiviral activity against coronaviruses. Here, we report the design, synthesis, and characterization of a novel series of INM-based PROTACs that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel of INM-based PROTACs was also enlarged by varying the linker moiety. The antiviral activity resulted very susceptible to this modification, particularly for PROTACs hijacking VHL as E3 ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 activity in infected human lung cells. Interestingly, degradation assays in both uninfected and virus-infected cells with the most promising PROTACs emerged so far (PROTACs 5 and 6) demonstrated that INM-PROTACs do not degrade human PGES-2 protein, as initially hypothesized, but induce the concentration-dependent degradation of SARS-CoV-2 main protease (M
MeSH term(s)	Humans ; Proteolysis ; Proteolysis Targeting Chimera ; COVID-19 ; SARS-CoV-2/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Antiviral Agents/pharmacology ; Coronavirus 3C Proteases
Chemical Substances	3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Proteolysis Targeting Chimera ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Antiviral Agents ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2024-02-06
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2024.116202
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Article ; Online: Development of an easy-to-set-up multiple heart-cutting achiral-chiral LC-LC method for the analysis of branched-chain amino acids in commercial tablets.

Varfaj, Ina / Abualzulof, Ghaid W A / Moretti, Simone / Migni, Anna / Uda, Irene / Goracci, Laura / Ianni, Federica / Carotti, Andrea / Sardella, Roccaldo

Electrophoresis

2024

Abstract: In this paper, the development and application of a multiple heart-cutting achiral-chiral LC-LC method (mLC-LC) for the analysis of dansylated (Dns) branched-chain amino acids in commercial tablets are described. In the first dimension, a Waters Xbridge ... ...

Abstract	In this paper, the development and application of a multiple heart-cutting achiral-chiral LC-LC method (mLC-LC) for the analysis of dansylated (Dns) branched-chain amino acids in commercial tablets are described. In the first dimension, a Waters Xbridge RP C18 achiral column was used under gradient conditions with buffered aqueous solution and acetonitrile. The elution order Dns-valine (Dns-Val) < Dns-isoleucine (Dns-Ile) < Dns-leucine (Dns-Leu) turned out with full resolution between adjacent peaks: 7.25 and 1.50 for the Val/Ile and the Ile/Leu pairs, respectively. A "research" validation study was performed, revealing high accuracy (Recovery%) and precision (RSD%) using two external set solutions, respectively, in the range 93.7%-104.1% and 0.4%-3.2%. The C18 column was connected via a two-position six-port switching valve to the quinidine-based Chiralpak quinidine-anion-exchange chiral column. A water/acetonitrile, 30/70 (v/v) with 50 mM ammonium acetate (apparent pH of 5.5) eluent allowed getting the three enantiomers' pairs resolved: R
Language	English
Publishing date	2024-03-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	619001-7
ISSN	1522-2683 ; 0173-0835
ISSN (online)	1522-2683
ISSN	0173-0835
DOI	10.1002/elps.202300278
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Article: PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

Desantis, Jenny / Mammoli, Andrea / Eleuteri, Michela / Coletti, Alice / Croci, Federico / Macchiarulo, Antonio / Goracci, Laura

RSC advances. 2022 Aug. 09, v. 12, no. 34

2022

Abstract: Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ... ...

Abstract	Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their physicochemical and pharmacokinetics properties. Considering the pivotal role played by the linker moiety, recently the insertion of a piperazine moiety into the PROTAC linker has been widely used, as this ring can in principle improve rigidity and increase solubility upon protonation. Nevertheless, the pKₐ of the piperazine ring is significantly affected by the chemical groups located nearby, and slight modifications in the linker could eliminate the desired effect. In the present study, the pKₐ values of a dataset of synthesized small molecule compounds including PROTACs and their precursors have been evaluated in order to highlight how a fine modulation of piperazine-containing linkers can impact the protonation state of these molecules or similar heterobifunctional ones. Finally, the possibility of predicting the trend through in silico approaches was also evaluated.
Keywords	computer simulation ; data collection ; moieties ; pharmacokinetics ; piperazine ; proteolysis ; protonation ; solubility ; therapeutics ; ubiquitination
Language	English
Dates of publication	2022-0809
Size	p. 21968-21977.
Publishing place	The Royal Society of Chemistry
Document type	Article
ISSN	2046-2069
DOI	10.1039/d2ra03761k
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

Desantis, Jenny / Mammoli, Andrea / Eleuteri, Michela / Coletti, Alice / Croci, Federico / Macchiarulo, Antonio / Goracci, Laura

RSC advances

2022 Volume 12, Issue 34, Page(s) 21968–21977

Abstract	Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their physicochemical and pharmacokinetics properties. Considering the pivotal role played by the linker moiety, recently the insertion of a piperazine moiety into the PROTAC linker has been widely used, as this ring can in principle improve rigidity and increase solubility upon protonation. Nevertheless, the p
Language	English
Publishing date	2022-08-09
Publishing country	England
Document type	Journal Article
ISSN	2046-2069
ISSN (online)	2046-2069
DOI	10.1039/d2ra03761k
Database	MEDical Literature Analysis and Retrieval System OnLINE

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