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LORENZO TAGLIAZUCCHI
CULTORE DELLA MATERIA
Dipartimento di Scienze della Vita sede ex Chimica V.Campi 103
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Pubblicazioni
2024
- Leveraging proteomic, bioinformatic and ecotoxicology models to select new targets overcoming L. Infantum drug resistent
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Brooks, Brain V.; Thorè, Eli S. J.; Bertram, Michael G.; Gammarro, Francisco; Costi, Maria Paola
abstract
2024
- Leveraging proteomics, bioinformatics, and ecotoxicology models to select new targets overcoming L infantum drug resistance.
[Relazione in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Brooks, Bryan W.; Thoré, Eli S. J.; Bertram, Michael G.; Gamarro, Francisco; Costi, Maria Paola
abstract
2024
- Precision medicine through proteomics studies in drug resistant colorectal cancer
[Abstract in Atti di Convegno]
Costi, Maria Paola; Piazzi, Manuela; Tagliazucchi, Lorenzo; Marverti, Gaetano; D’Arca, Domenico; Moschella, MARIA GAETANA; Losi, Lorena; Bedeschi, Martina; Tesei, Anna; Passardi, Alessandro
abstract
2023
- A dual-Omics approach to identify the modulated proteins/genes in THP-1 cells infected with different drug resistant L. infantum clinical isolates.
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Perea-Martinez, Ana; Fiorini, Greta; Ignacio Manzano, José; García-Hernández, Raquel; Genovese, Filippo; Pinetti, Diego; Gamarro, Francisco; Costi, Maria Paola
abstract
2023
- Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery-Genetics Alliance Perspective
[Articolo su rivista]
Pozzi, Cecilia; Vanet, Anne; Francesconi, Valeria; Tagliazucchi, Lorenzo; Tassone, Giusy; Venturelli, Alberto; Spyrakis, Francesca; Mazzorana, Marco; Costi, Maria P; Tonelli, Michele
abstract
: The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host-pathogen interactions and adaptation, leading to drug resistance phenomena. Herein, we will explore how the study of observed and predicted mutations may offer valuable suggestions for the application of the so-called "synthetic lethal" strategy to SARS-CoV-2 Main protease and Spike protein. The synergy between genetics evidence and drug discovery may prioritize the development of novel long-lasting antiviral agents.
2023
- Applying optical tweezers technology to reveal Thymidylate Synthase interactions with its consensus mRNA
[Abstract in Atti di Convegno]
Malpezzi, Giulia; Viader, Xvaier; Zaltron, Annamaria; Neri, Benedetta; di Felice, Giulia; Tagliazucchi, Lorenzo; Aiello, Daniele; Moschella, MARIA GAETANA; Costi, Maria Paola; D'Arca, Domenico; Cecconi, Ciro
abstract
2023
- Development of a novel class of YAP:TEAD interface-3 molecular disruptors to treat colorectal carcinoma
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Aiello, Daniele; Zappaterra, Dana; Elisi, GIAN MARCO; Venturelli, Alberto; Moschella, MARIA GAETANA; D'Arca, Domenico; Marverti, Gaetano; Lopresti, Ludovica; Pozzi, Cecilia; Pacifico, Salvatore; Guerrini, Remo; Ponterini, Glauco; Costi, Maria Paola
abstract
2023
- EXPLOITING THE OPTICAL TWEEZER, A SINGLE MOLECULE TECHNOLOGY, TO REVEAL THYMIDYLATE SYNTHASE INTERACTIONS WITH ITS CONSENSUS mRNA
[Abstract in Atti di Convegno]
Malpezzi, Giulia; Viander, Xavier; Zaltron, Annamaria; Neri, Benedetta; Di Felice, Giulia; Tagliazucchi, Lorenzo; Aiello, Daniele; Moschella, Maria; Costi, Maria Paola; D’Arcae, Domenico; Cecconi, Ciro
abstract
2023
- Exploiting the Optical Tweezer technology to reveal thymidylate synthase
interactions with its consensus mRNA
[Abstract in Atti di Convegno]
Malpezzi, Giulia; Viander, Xavier; Zaltron, Annamaria; Neri, Benedetta; Di Felice, Giulia; Tagliazucchi, Lorenzo; Aiello, Daniele; Moschella, MARIA GAETANA; Costi, Maria Paola; D'Arca, Domenico; Cecconi, Ciro
abstract
2023
- Insights into host-target interaction from the proteome modulation analysis through untargeted LC-MS/MS Proteomics of drug resistant L infantum-THP1 infected cells
[Relazione in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Perea Martinez, Ana; Ignacio Manzano, José; Garcia-Hernandez, Raquel; Pinetti, Diego; Genovese, Filippo; Thorè, Eli; Brooks, Bryan W.; Bertram, Michael G.; Gamarro, Francisco; Costi, Maria Paola
abstract
2023
- Investigating the mechanism of action of the antiparasitic agent H80 through
imaging techniques
[Abstract in Atti di Convegno]
Malpezzi, Giulia; Tagliazucchi, Lorenzo; Aiello, Daniele; Venturelli, Alberto; CORDEIRO DA SILVA, Anabela; Santarem, Nuno; Ponterini, Glauco; Costi, Maria Paola
abstract
2023
- LC-MS/MS proteomics for the rapid and selective screening of drug resistances in Leishmania infantum clinical isolates
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Perea Martinez, Ana; Ignacio Manzano, José; Garcia-Hernandez, Raquel; Pinetti, Diego; Genovese, Filippo; Costi, Maria Paola
abstract
2023
- Label-Free Mass Spectrometry Proteomics Reveals Different Pathways Modulated in THP-1 Cells Infected with Therapeutic Failure and Drug Resistance Leishmania infantum Clinical Isolates
[Articolo su rivista]
Tagliazucchi, Lorenzo; Perea-Martinez, Ana; Fiorini, Greta; Ignacio Manzano, José; Genovese, Filippo; García-Hernández, Raquel; Pinetti, Diego; GAMARRO CONDE, Francisco; Costi, Maria Paola
abstract
2023
- Lead optimization of human thymidylate synthase dimer disrupters: from computational studies to evaluation of their biological profiles
[Abstract in Atti di Convegno]
Aiello, Daniele; Malpezzi, Giulia; Tagliazucchi, Lorenzo; Moschella, MARIA GAETANA; Giulia, Saporito; Venturelli, Alberto; Gluaco, Ponterini; D'Arca, Domenico; Marverti, Gaetano; Federico, Falchi; Costi, Maria Paola
abstract
2023
- Serum Mass Spectrometry Proteomics and Protein Set Identification in Response to FOLFOX-4 in Drug-Resistant Ovarian Carcinoma
[Articolo su rivista]
D'Arca, Domenico; Severi, Leda; Ferrari, Stefania; Dozza, Luca; Marverti, Gaetano; Magni, Fulvio; Chinello, Clizia; Pagani, Lisa; Tagliazucchi, Lorenzo; Villani, Marco; D'Addese, Gianluca; Piga, Isabella; Conteduca, Vincenza; Rossi, Lorena; Gurioli, Giorgia; De Giorgi, Ugo; Losi, Lorena; Costi, Maria Paola
abstract
2023
- The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents
[Articolo su rivista]
Linciano, Pasquale; Pozzi, Cecilia; Tassone, Giusy; Landi, Giacomo; Mangani, Stefano; Santucci, Matteo; Luciani, Rosaria; Ferrari, Stefania; Santarem, Nuno; Tagliazucchi, Lorenzo; Cordeiro-da-Silva, Anabela; Tonelli, Michele; Tondi, Donatella; Bertarini, Laura; Gul, Sheraz; Witt, Gesa; Moraes, Carolina B; Costantino, Luca; Costi, Maria Paola
abstract
2023
- design, synthesis and biological evaluation of novel YAP:TEAD complex disruptors for thetreatment of colorectal cancer
[Relazione in Atti di Convegno]
Tagliazucchi, Lorenzo; Venturelli, Alberto; Malpezzi, Giulia; Zappaterra, Dana; Aiello, Daniele; Elisi, GIAN MARCO; Mor, Marco; Moschella, MARIA GAETANA; Marverti, Gaetano; D'Arca, Domenico; Ponterini, Glauco; Costi, Maria Paola
abstract
2022
- A toolbox of biophysical and analytical assays helps to confirm the activity of novel hTS dimer disrupters (Ddis) with anticancer properties
[Poster]
Tagliazucchi, Lorenzo; Venturelli, Alberto; Malpezzi, Giulia; Moschella, MARIA GAETANA; Aiello, Daniele; Lopresti, Ludovica; Pozzi, Cecilia; Marverti, Gaetano; D'Arca, Domenico; Ponterini, Glauco; Costi, Maria Paola
abstract
2022
- Characterization and Valorization of the Agricultural Waste Obtained from Lavandula Steam Distillation for Its Reuse in the Food and Pharmaceutical Fields
[Articolo su rivista]
Truzzi, Eleonora; Chaouch, Mohamed Aymen; Rossi, Gaia; Tagliazucchi, Lorenzo; Bertelli, Davide; Benvenuti, Stefania
abstract
2022
- Current Treatments to Control African Trypanosomiasis and One Health Perspective
[Articolo su rivista]
Venturelli, Alberto; Tagliazucchi, Lorenzo; Lima, Clara; Venuti, Federica; Malpezzi, Giulia; Magoulas, George E.; Santarem, Nuno; Calogeropoulou, Theodora; Cordeiro-da-Silva, Anabela; Costi, Maria Paola
abstract
2022
- Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth
[Articolo su rivista]
Costantino, Luca; Ferrari, Stefania; Santucci, Matteo; MH Salo-Ahen, Outi; Carosati, Emanuele; Franchini, Silvia; Lauriola, Angela; Pozzi, Cecilia; Trande, Matteo; Gozzi, Gaia; Saxena, Puneet; Cannazza, Giuseppe; Losi, Lorena; Cardinale, Daniela; Venturelli, Alberto; Quotadamo, Antonio; Linciano, Pasquale; Tagliazucchi, Lorenzo; Moschella, MARIA GAETANA; Guerrini, Remo; Pacifico, Salvatore; Luciani, Rosaria; Genovese, Filippo; Henrich, Stefan; Alboni, Silvia; Santarem, Nuno; CORDEIRO DA SILVA, Anabela; Giovannetti, Elisa; J Peters, Godefridus; Pinton, Paolo; Rimessi, Alessandro; Cruciani, Gabriele; M Stroud, Robert; C Wade, Rebecca; Mangani, Stefano; Marverti, Gaetano; D'Arca, Domenico; Ponterini, Glauco; Costi, Maria Paola
abstract
2022
- Development of a sensitive biochemical tool to assess the expression levels of recombinant ectopic proteins in in vitro engineered cellular systems
[Abstract in Atti di Convegno]
Moschella, Mg; Marverti, G; Cassanelli, Valentina; Venuti, Federica; Tagliazucchi, L; Costi, Mp; D’Arca., D
abstract
2022
- Discovery of guanidino-containing benzimidazoles as novel antifolates for Trypanosomiasis
[Abstract in Atti di Convegno]
Francesconi, Valeria; Rizzo, Marco; Tagliazucchi, Lorenzo; Pozzi, Cecilia; CORDEIRO DA SILVA, Anabela; Venuti, Federica; Konchie, Claude; Costi, Maria Paola; Michele, Tonelli
abstract
2022
- Exploiting Forster Resonance Energy Transfer (FRET) in the characterization of YAP:TEAD complex disruption
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Rossi, Marianna; Malpezzi, Giulia; Zappaterra, Dana; Aiello, Daniele; Pozzi, Cecilia; Pacifico, Salvatore; Guerrini, Remo; Venturelli, Alberto; Ponterini, Glauco; Costi, Maria Paola
abstract
2022
- Expression, purification, and characterization of Transcriptional Enhancer Associated Domain (hTEAD4), a promising target for anticancer agents
[Abstract in Atti di Convegno]
Tagliazucchi, L; Rossi, Marianna; Pozzi, Cecilia; Lopresti, Ludovica; Aiello, D; Venturelli, A; Ponterini, G; Costi, Mp
abstract
2022
- Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library
[Articolo su rivista]
Lauriola, A.; Uliassi, E.; Santucci, M.; Bolognesi, M. L.; Mor, M.; Scalvini, L.; Elisi, G. M.; Gozzi, G.; Tagliazucchi, L.; Marverti, G.; Ferrari, S.; Losi, L.; D'Arca, D.; Costi, M. P.
abstract
The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.
2022
- LC-MS serum proteomics reveals a panel of proteins prognostic of positive responsiveness to bevacizumab therapy in late-stages ovarian cancer patients
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Moschella, MARIA GAETANA; D'Addese, Gianluca; Califano, Daniela; Arenare, Laura; Mezzanzanico, Delia; Chinello, Clizia; Magni, Fulvio; Villani, Marco; Losi, Lorena; Marverti, Gaetano; D'Arca, Domenico; Chiodini, Paolo; Pignata, Sandro; Costi, Maria Paola
abstract
2022
- LC-MS/MS Helps Characterizing THP-1 Cells Proteome After Infection with Drug Resistant Leishmania Strains
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Perea-Martinez, Ana; Fiorini, Greta; Ignacio Manzano, José; García-Hernández, Raquel; Genovese, Filippo; Pinetti, Diego; Gamarro, Francisco; Costi, Maria Paola
abstract
2022
- Lead-optimization process and characterization of the dissociative effect applied to new dimer disrupters of human Thymidylate Synthase
[Abstract in Atti di Convegno]
Aiello, Daniele; Ascione, Cristian; Tagliazucchi, Lorenzo; Malpezzi, Giulia; Cassanelli, Valentina; Ponterini, Glauco; D'Arca, Domenico; Marverti, Gaetano; Moschella, MARIA GAETANA; Falchi, Federico; Venturelli, Alberto; Costi, Maria Paola
abstract
2022
- Targeting the dimer-monomer equilibrium of thymidylate synthase, to accelerate protein degradation and cancer cell growth inhibition
[Abstract in Atti di Convegno]
Costi, Maria Paola; Venturelli, A; Ponterini, G; Pozzi, C; Wade, Rebecca; Giovannetti, E; Rimessi, A; Tagliazucchi, L; Moschella, M; Marverti, G; D’Arca, D
abstract
2021
- Cellular uptake and metabolic degradation of a conjugate of folic acid with an anticancer peptide targeting the human Thymidylate synthase enzyme
[Relazione in Atti di Convegno]
Tagliazucchi, Lorenzo; Marverti, Gaetano; D'Arca, Domenico; Ponterini, Glauco; Costi, Maria Paola
abstract
2021
- Coupling a microwave-assisted process with HPLC-ELSD for the extraction, purification and analysis of bioactive policosanols from beeswax
[Abstract in Atti di Convegno]
Venturelli, Alberto; Brighenti, Virginia; Tagliazucchi, Lorenzo; Costi, Maria Paola; Pellati, Federica
abstract
2021
- Designing selective Cys-ligands to unpair the binding of the Human Transcription Enhancer Associated Domain 4 (hTEAD-4) with its modulators to halt cancer cell growth
[Poster]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Pozzi, Cecilia; Lopresti, Ludovica; Venturelli, Alberto; D'Arca, Domenico; Marverti, Gaetano; Cecconi, Ciro; Ponterini, Glauco; Costi, Maria Paola
abstract
The Hippo Signalling cascade is an emerging target in tumour suppression regulation, neoplastic hypertrophy, and regenerative medicine. The pathway is activated by circulating anti-proliferative signals which leads to the phosphorylation of Yes Associated Protein (hYAP1) on Ser127/381, thus 14-3-3σ mediated cytosolic retention. Genetic alterations or exogenous factor may cause YAP nuclear migration and association to TEAD1-4 (Transcription Enhancer Associated Domain), triggering up-regulation of anti-apoptotic genes [1]. hTEAD is an enhancer that activates the nuclear transcription of genes as EMT’s, EGFR and cyclins, and promotes the synthesis of survivin, tyrosine kinase HER3, and mitochondrial Bcl-xL involved in cell proliferation. TEAD binds a palmitic (palm) or myristic (myr) acids, tethered at Cys367 pocket, however its biological role is still not well known. hTEAD isoform-4 is the most represented of its family in solid tumours and its overexpression or mutation leads to cancer development and metastasis. Recent studies have considered hTEAD a promising target for anticancer drugs. Its inhibition strategy includes the disruption/prevention of YAP1:TEAD4 complex formation [2]. With the aim to develop a specific cysteine-directed inhibition strategy, we studied Cys on the protein surface and investigated their reactivity. Hence, our studies focus on characterizing the recombinant hTEAD4-ybd (aa217-434) surface though the analysis of the reactivity of its four Cys thiols (Cys310, Cys335, Cys367, Cys410), all close to YAP binding area. First, myr-Cys-367 was investigated to confirm the auto-myristoilation of the E. coli recombinant hTEAD4 through RP-chromatography on UHPLC-Orbitrap Q-Ex (ThermoFisher™) by multicharged TIC deconvolution, and the total myr-TEAD was assessed around 25%. Myristate position was confirmed by FASP protein tryptic hydrolysis and tandem-MS peptide analysis. We studied hTEAD binding of a small disulphides and thiols library with different chemical properties through the exposed cysteines residues in presence of different concentration of reducing agent [3]. Top8 DDA (HCD)-MS/MS scan on the tryptic peptides suggested the ligands’ high selectivity towards Cys335. Cys367 was never found conjugated, even in the non-Myr fraction, hinting the low accessibility to the lipid pocket. The number of surface reactive Cys was confirmed by a reverse-titration of the protein against increasing amount of thiophenol; excess of unreacted thiophenol was measured by HPLC-UV-ELSD (Agilent™ 1260), suggesting a 1:1 stoichiometry. We confirmed hTEAD-ybd ligand ratio by fluoresceine labelling with absorption and fluorescence differential spectroscopy. The ongoing work engages the screening of a larger compound library to study YAP:TEAD interaction with a ligand displacement assay of labelled TEAD to a rhodamine-tagged peptidomimetic probe to achieve structural information of the heterodimer interface and to start a hit-optimization programme.
REFERENCES
[1] Santucci M, Vignudelli T, et al. The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment. J Med Chem. 2015 Jun 25;58(12):4857-73.
[2] Elisi G.M, Santucci M, et al. Repurposing of Drugs Targeting YAP-TEAD Functions. Cancers 2018, 10, 329.
[3] Malpezzi G MSc Degree Thesis, Solvent exposure, and reactivity of the cysteines of Transcription Enhancer Associate Domain (TEAD), a potential anticancer target, 2021. University of Pavia – University of Modena and Reggio Emilia.
2021
- Development of guanidino-containing benzimidazoles as novel folate enzymes inhibitors for the treatment of Human African Trypanosomiasis
[Abstract in Atti di Convegno]
Rizzo, Marco; Francesconi, Valeria; Cichero, Elena; Schenone, Silvia; Tagliazucchi, Lorenzo; Cordeiro da Silva, Anabela; Costi, Maria Paola; Tonelli, Michele
abstract
2021
- Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase
[Articolo su rivista]
Tassone, Giusy; Landi, Giacomo; Linciano, Pasquale; Francesconi, Valeria; Tonelli, Michele; Tagliazucchi, Lorenzo; Costi, Maria Paola; Mangani, Stefano; Pozzi, Cecilia
abstract
Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.
2021
- Folic Acid-Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting
[Articolo su rivista]
Marverti, Gaetano; Marraccini, Chiara; Martello, Andrea; D'Arca, Domenico; Pacifico, Salvatore; Guerrini, Remo; Spyrakis, Francesca; Gozzi, Gaia; Lauriola, Angela; Santucci, Matteo; Cannazza, Giuseppe; Tagliazucchi, Lorenzo; Cazzato, Addolorata Stefania; Losi, Lorena; Ferrari, Stefania; Ponterini, Glauco; Costi, Maria P
abstract
Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor alpha (FRalpha) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRalpha selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.
2021
- Proteomic contribution to the omic path for the identification of novel drugs overcoming resistance in Leishmaniasis.
[Relazione in Atti di Convegno]
Tagliazucchi, Lorenzo; Fiorini, Greta; Perea-Martínez, Ana; García- Hernández, Raquel; Ignacio Manzano, José; Costi, Maria Paola; Gamarro, Francisco
abstract
2021
- Repurposing the trypanosomatidic gsk kinetobox for the inhibition of parasitic pteridine and dihydrofolate reductases
[Articolo su rivista]
Santucci, M.; Luciani, R.; Gianquinto, E.; Pozzi, C.; Di Pisa, F.; Dello Iacono, L.; Landi, G.; Tagliazucchi, L.; Mangani, S.; Spyrakis, F.; Costi, M. P.
abstract
Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypanosoma brucei and Lesihmania major parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors). Molecular docking studies of the protein–ligand interaction focused on new scaffolds not reproducing the well-known antifolate core clearly explaining the experimental data. TCMDC-143249, classified as a benzenesulfonamide derivative by the QikProp descriptor tool, showed selective inhibition of PTR1 and growth inhibition of the kinetoplastid parasites in the 5 µM range. In our work, we enlarged the biological profile of the GSK Kinetobox and identified new core structures inhibiting selectively PTR1, effective against the kinetoplastid infectious protozoans. In perspective, we foresee the development of selective PTR1 and DHFR inhibitors for studies of drug combinations.
2021
- Structural bases for the synergistic inhibition of human thymidylate synthase and ovarian cancer cell growth by drug combinations
[Articolo su rivista]
Pozzi, C.; Santucci, M.; Marverti, G.; D'arca, D.; Tagliazucchi, L.; Ferrari, S.; Gozzi, G.; Losi, L.; Tassone, G.; Mangani, S.; Ponterini, G.; Costi, M. P.
abstract
2021
- Structural insight into YAP-TEAD4 protein-protein interactions as target for cancer treatment
[Abstract in Atti di Convegno]
Lopresti, Ludovica; Pozzi, Cecilia; Tagliazucchi, L; D’Arca, D; Marverti, G; Costi, Mp; Mangani, Stefano
abstract
2021
- Targeting of the Cysteines Surface domain of the Transcriptional Enhancer Associate Domain (TEAD) for anticancer drug discovery
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Mangani, Stefano; Lopresti, Ludovica; Pozzi, Cecilia; Ponterini, Glauco; Venturelli, Alberto; Costi, Maria Paola
abstract
2021
- UHPLC-MS/MS screening of the hTEAD surface for the identification of novel allosteric inhibitors with anticancer activity
[Abstract in Atti di Convegno]
Tagliazucchi, Lorenzo; Malpezzi, Giulia; Pozzi, Cecilia; Lopresti, Ludovica; Mangani, Stefano; ABDEL LATIF, Andrea; Ponterini, Glauco; Venturelli, Alberto; Costi, Maria Paola
abstract
2019
- Advances in the set-up of a fluorescence- anisotropy assay for the search of novel inhibitors of the tead-4 complexes
[Abstract in Atti di Convegno]
Romito, Filippo; Tagliazucchi, Lorenzo; Pozzi, Cecilia; Mangani, Stefano; Lopresti, Ludovica; Ponterini, Glauco; Costi, Maria Paola
abstract