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Article ; Online: Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging.

Grillberger, Karin / Cöllen, Eike / Trivisani, Claudia Immacolata / Blum, Jonathan / Leist, Marcel / Ecker, Gerhard F

International journal of molecular sciences

2023 Volume 24, Issue 17

Abstract: Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the ... ...

Abstract	Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT).
MeSH term(s)	Animals ; Humans ; Calcium ; Molecular Docking Simulation ; Calcium, Dietary ; Neonicotinoids/pharmacology ; Receptors, Nicotinic
Chemical Substances	Calcium (SY7Q814VUP) ; Calcium, Dietary ; Neonicotinoids ; Receptors, Nicotinic
Language	English
Publishing date	2023-08-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241713170
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Article ; Online: Progress towards Adjuvant Development: Focus on Antiviral Therapy.

Brai, Annalaura / Poggialini, Federica / Pasqualini, Claudia / Trivisani, Claudia Immacolata / Vagaggini, Chiara / Dreassi, Elena

International journal of molecular sciences

2023 Volume 24, Issue 11

Abstract: In recent decades, vaccines have been extraordinary resources to prevent pathogen diffusion and cancer. Even if they can be formed by a single antigen, the addition of one or more adjuvants represents the key to enhance the response of the immune signal ... ...

Abstract	In recent decades, vaccines have been extraordinary resources to prevent pathogen diffusion and cancer. Even if they can be formed by a single antigen, the addition of one or more adjuvants represents the key to enhance the response of the immune signal to the antigen, thus accelerating and increasing the duration and the potency of the protective effect. Their use is of particular importance for vulnerable populations, such as the elderly or immunocompromised people. Despite their importance, only in the last forty years has the search for novel adjuvants increased, with the discovery of novel classes of immune potentiators and immunomodulators. Due to the complexity of the cascades involved in immune signal activation, their mechanism of action remains poorly understood, even if significant discovery has been recently made thanks to recombinant technology and metabolomics. This review focuses on the classes of adjuvants under research, recent mechanism of action studies, as well as nanodelivery systems and novel classes of adjuvants that can be chemically manipulated to create novel small molecule adjuvants.
MeSH term(s)	Humans ; Aged ; Adjuvants, Immunologic/pharmacology ; Vaccines ; Immunologic Factors ; Adjuvants, Pharmaceutic ; Antiviral Agents/pharmacology
Chemical Substances	Adjuvants, Immunologic ; Vaccines ; Immunologic Factors ; Adjuvants, Pharmaceutic ; Antiviral Agents
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24119225
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Article ; Online: DEAD-Box Helicase DDX3X as a Host Target against Emerging Viruses: New Insights for Medicinal Chemical Approaches.

Brai, Annalaura / Trivisani, Claudia Immacolata / Poggialini, Federica / Pasqualini, Claudia / Vagaggini, Chiara / Dreassi, Elena

Journal of medicinal chemistry

2022 Volume 65, Issue 15, Page(s) 10195–10216

Abstract: In recent years, globalization, global warming, and population aging have contributed to the spread of emerging viruses, such as coronaviruses (COVs), West Nile (WNV), Dengue (DENV), and Zika (ZIKV). The number of reported infections is increasing, and ... ...

Abstract	In recent years, globalization, global warming, and population aging have contributed to the spread of emerging viruses, such as coronaviruses (COVs), West Nile (WNV), Dengue (DENV), and Zika (ZIKV). The number of reported infections is increasing, and considering the high viral mutation rate, it is conceivable that it will increase significantly in the coming years. The risk caused by viruses is now more evident due to the COVID-19 pandemic, which highlighted the need to find new broad-spectrum antiviral agents able to tackle the present pandemic and future epidemics. DDX3X helicase is a host factor required for viral replication. Selective inhibitors have been identified and developed into broad-spectrum antivirals active against emerging pathogens, including SARS-CoV-2 and most importantly against drug-resistant strains. This perspective describes the inhibitors identified in the last years, highlighting their therapeutic potential as innovative broad-spectrum antivirals.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19 ; DEAD-box RNA Helicases ; Humans ; Pandemics ; SARS-CoV-2 ; Virus Replication ; Viruses ; Zika Virus ; Zika Virus Infection
Chemical Substances	Antiviral Agents ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2022-07-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c00755
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Article: Discovery and Optimization of a Novel Macrocyclic Amidinourea Series Active as Acidic Mammalian Chitinase Inhibitors.

Balestri, Lorenzo Jacopo Ilic / Trivisani, Claudia Immacolata / Orofino, Francesco / Fiorucci, Diego / Truglio, Giuseppina Ivana / D'Agostino, Ilaria / Poggialini, Federica / Botta, Lorenzo / Docquier, Jean-Denis / Dreassi, Elena

ACS medicinal chemistry letters

2023 Volume 14, Issue 4, Page(s) 417–424

Abstract: Our research group has been involved for a long time in the development of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic investigation drove us to perform ... ...

Abstract	Our research group has been involved for a long time in the development of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic investigation drove us to perform an
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.2c00472
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Article ; Online: Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma.

Rango, Enrico / D'Antona, Lucia / Iovenitti, Giulia / Brai, Annalaura / Mancini, Arianna / Zamperini, Claudio / Trivisani, Claudia Immacolata / Marianelli, Stefano / Fallacara, Anna Lucia / Molinari, Alessio / Cianciusi, Annarita / Schenone, Silvia / Perrotti, Nicola / Dreassi, Elena / Botta, Maurizio

European journal of medicinal chemistry

2021 Volume 223, Page(s) 113653

Abstract: Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water ...

Abstract	Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Stability ; Female ; Fibrinolysin/metabolism ; Half-Life ; Humans ; Immediate-Early Proteins/antagonists & inhibitors ; Immediate-Early Proteins/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Mice ; Mice, Nude ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Paclitaxel/pharmacology ; Paclitaxel/therapeutic use ; Prodrugs/chemistry ; Prodrugs/metabolism ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Transplantation, Heterologous
Chemical Substances	Antineoplastic Agents ; Immediate-Early Proteins ; Prodrugs ; Pyrazoles ; Pyrimidines ; pyrazolo(3,4-d)pyrimidine (271-80-7) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; serum-glucocorticoid regulated kinase (EC 2.7.11.1) ; Fibrinolysin (EC 3.4.21.7) ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2021-06-17
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.2021.113653
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Article ; Online: Novel alternative ribonucleotide excision repair pathways in human cells by DDX3X and specialized DNA polymerases.

Riva, Valentina / Garbelli, Anna / Casiraghi, Federica / Arena, Francesca / Trivisani, Claudia Immacolata / Gagliardi, Assunta / Bini, Luca / Schroeder, Martina / Maffia, Antonio / Sabbioneda, Simone / Maga, Giovanni

Nucleic acids research

2020 Volume 48, Issue 20, Page(s) 11551–11565

Abstract: Removal of ribonucleotides (rNMPs) incorporated into the genome by the ribonucleotide excision repair (RER) is essential to avoid genetic instability. In eukaryotes, the RNaseH2 is the only known enzyme able to incise 5' of the rNMP, starting the RER ... ...

Abstract	Removal of ribonucleotides (rNMPs) incorporated into the genome by the ribonucleotide excision repair (RER) is essential to avoid genetic instability. In eukaryotes, the RNaseH2 is the only known enzyme able to incise 5' of the rNMP, starting the RER process, which is subsequently carried out by replicative DNA polymerases (Pols) δ or ϵ, together with Flap endonuclease 1 (Fen-1) and DNA ligase 1. Here, we show that the DEAD-box RNA helicase DDX3X has RNaseH2-like activity and can support fully reconstituted in vitro RER reactions, not only with Pol δ but also with the repair Pols β and λ. Silencing of DDX3X causes accumulation of rNMPs in the cellular genome. These results support the existence of alternative RER pathways conferring high flexibility to human cells in responding to the threat posed by rNMPs incorporation.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Catalytic Domain ; Cell Line ; DEAD-box RNA Helicases/chemistry ; DEAD-box RNA Helicases/metabolism ; DNA Polymerase beta/metabolism ; Humans ; Protein Domains ; RNA-Binding Motifs ; Ribonuclease H/chemistry ; Ribonuclease H/metabolism ; Ribonucleotides/metabolism
Chemical Substances	Ribonucleotides ; Adenosine Triphosphate (8L70Q75FXE) ; DNA polymerase beta2 (EC 2.7.7.-) ; DNA Polymerase beta (EC 2.7.7.7) ; ribonuclease HII (EC 3.1.26.-) ; Ribonuclease H (EC 3.1.26.4) ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2020-11-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa948
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Article ; Online: Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X.

Brai, Annalaura / Ronzini, Stefania / Riva, Valentina / Botta, Lorenzo / Zamperini, Claudio / Borgini, Matteo / Trivisani, Claudia Immacolata / Garbelli, Anna / Pennisi, Carla / Boccuto, Adele / Saladini, Francesco / Zazzi, Maurizio / Maga, Giovanni / Botta, Maurizio

Molecules (Basel, Switzerland)

2019 Volume 24, Issue 21

Abstract: The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its ... ...

Abstract	The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.
MeSH term(s)	Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; DEAD-box RNA Helicases/antagonists & inhibitors ; HIV-1/drug effects ; Humans ; Thiadiazoles/chemistry ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Thiadiazoles ; 1,3,4-thiadiazole (14IAC3GH7G) ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2019-11-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules24213988
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Article: Exploring the Implication of DDX3X in DENV Infection: Discovery of the First-in-Class DDX3X Fluorescent Inhibitor.

Brai, Annalaura / Boccuto, Adele / Monti, Martina / Marchi, Serena / Vicenti, Ilaria / Saladini, Francesco / Trivisani, Claudia Immacolata / Pollutri, Alessandro / Trombetta, Claudia Maria / Montomoli, Emanuele / Riva, Valentina / Garbelli, Anna / Nola, Emanuele Maria / Zazzi, Maurizio / Maga, Giovanni / Dreassi, Elena / Botta, Maurizio

ACS medicinal chemistry letters

2020 Volume 11, Issue 5, Page(s) 956–962

Abstract: In the absence of effective drugs or vaccines for the treatment of the five Dengue Virus serotypes, the search for novel antiviral drugs is of primary importance for the scientific community. In this context, drug repurposing represents the most used ... ...

Abstract	In the absence of effective drugs or vaccines for the treatment of the five Dengue Virus serotypes, the search for novel antiviral drugs is of primary importance for the scientific community. In this context, drug repurposing represents the most used strategy; however, the study of host targets is now attracting attention since it allows identification of broad-spectrum drugs endowed with high genetic barrier. In the last ten years our research group identified several small molecules DDX3X inhibitors and proved their efficacy against different viruses including novel emerging ones. Herein, starting from a screening of our compounds, we designed and synthesized novel derivatives with potent activity and high selectivity. Finally, we synthesized a fluorescent inhibitor that allowed us to study DDX3X cellular localization during DENV infection
Language	English
Publishing date	2020-04-09
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.9b00681
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Article ; Online: DDX3X inhibitors, an effective way to overcome HIV-1 resistance targeting host proteins.

Brai, Annalaura / Riva, Valentina / Saladini, Francesco / Zamperini, Claudio / Trivisani, Claudia Immacolata / Garbelli, Anna / Pennisi, Carla / Giannini, Alessia / Boccuto, Adele / Bugli, Francesca / Martini, Maurizio / Sanguinetti, Maurizio / Zazzi, Maurizio / Dreassi, Elena / Botta, Maurizio / Maga, Giovanni

European journal of medicinal chemistry

2020 Volume 200, Page(s) 112319

Abstract: The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people ... ...

Abstract	The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people living with HIV. However, life-long treatments could result in the emergence of drug-resistant viruses that can progressively reduce the number of therapeutic options, facilitating the progression of the disease. In this scenario, we previously demonstrated that inhibitors of the human DDX3X helicase can represent an innovative approach for the simultaneous treatment of HIV and other viral infections such as Hepatitis c virus (HCV). We reported herein 6b, a novel DDX3X inhibitor that thanks to its distinct target of action is effective against HIV-1 strains resistant to currently approved drugs. Its improved in vitro ADME properties allowed us to perform preliminary in vivo studies in mice, which highlighted optimal biocompatibility and an improved bioavailability. These results represent a significant advancement in the development of DDX3X inhibitors as a novel class of broad spectrum and safe anti-HIV-1 drugs.
MeSH term(s)	Animals ; Anti-HIV Agents/chemistry ; Anti-HIV Agents/pharmacology ; DEAD-box RNA Helicases/antagonists & inhibitors ; Drug Resistance, Viral/drug effects ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; HIV-1/physiology ; Humans ; Mice ; Virus Diseases/drug therapy
Chemical Substances	Anti-HIV Agents ; Enzyme Inhibitors ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2020-05-07
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.2020.112319
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Article: Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.

Cancers

2021 Volume 13, Issue 21

Abstract: DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series ... ...

Abstract	DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.
Language	English
Publishing date	2021-11-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13215569
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