11 results on '"Minotti, Alberto"'
Search Results
2. Synthetic glycolipids as molecular vaccine adjuvants: mechanism of action in human cells and in vivo activity
- Author
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European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Facchini, Fabio A. [0000-0002-4339-5845], Minotti, Alberto [0000-0002-0443-6472], Luraghi, Andrea [0000-0002-9452-7561], Matamoros-Recio, Alejandra [0000-0003-1563-9408], Iannucci, Andrea [0000-0001-5194-8959], Wang, Guanbo [0000-0001-8210-8805], Ingram, Rebecca [0000-0003-1832-2457], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Pirianov, Grisha [0000-0002-6480-7765], De Andrea, Marco [0000-0002-3188-5783], Valvano, Miguel A. [0000-0001-8229-3641], Peri, Francesco [0000-0002-3417-8224], Facchini, Fabio A., Minotti, Alberto, Luraghi, Andrea, Romerio, Alessio, Gotri, Nicole, Matamoros-Recio, Alejandra, Iannucci, Andrea, Palmer, Charys, Wang, Guanbo, Ingram, Rebecca, Martín-Santamaría, Sonsoles, Pirianov, Grisha, De Andrea, Marco, Valvano, Miguel A., Peri, Francesco, European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Facchini, Fabio A. [0000-0002-4339-5845], Minotti, Alberto [0000-0002-0443-6472], Luraghi, Andrea [0000-0002-9452-7561], Matamoros-Recio, Alejandra [0000-0003-1563-9408], Iannucci, Andrea [0000-0001-5194-8959], Wang, Guanbo [0000-0001-8210-8805], Ingram, Rebecca [0000-0003-1832-2457], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Pirianov, Grisha [0000-0002-6480-7765], De Andrea, Marco [0000-0002-3188-5783], Valvano, Miguel A. [0000-0001-8229-3641], Peri, Francesco [0000-0002-3417-8224], Facchini, Fabio A., Minotti, Alberto, Luraghi, Andrea, Romerio, Alessio, Gotri, Nicole, Matamoros-Recio, Alejandra, Iannucci, Andrea, Palmer, Charys, Wang, Guanbo, Ingram, Rebecca, Martín-Santamaría, Sonsoles, Pirianov, Grisha, De Andrea, Marco, Valvano, Miguel A., and Peri, Francesco
- Abstract
Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA.
- Published
- 2021
3. Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity
- Author
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Facchini, Fabio A., primary, Minotti, Alberto, additional, Luraghi, Andrea, additional, Romerio, Alessio, additional, Gotri, Nicole, additional, Matamoros-Recio, Alejandra, additional, Iannucci, Andrea, additional, Palmer, Charys, additional, Wang, Guanbo, additional, Ingram, Rebecca, additional, Martin-Santamaria, Sonsoles, additional, Pirianov, Grisha, additional, De Andrea, Marco, additional, Valvano, Miguel A., additional, and Peri, Francesco, additional
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- 2021
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- View/download PDF
4. Structure-activity relationship (SAR) in monosaccharide-based Toll-like receptor 4 (TLR4) antagonists
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Facchini, Fabio A, Zaffaroni, Lenny, Minotti, Alberto, Rapisarda, Silvia, Calabrese, Valentina, Forcella, Matilde, Fusi, Paola, Airoldi, Cristina, Ciaramelli, Carlotta, Billod, Jean-Marc, Schromm, Andra, Braun, Harald, Palmer, Charys, Beyaert, Rudi, Jerala, Roman, Pirianov, Grisha, Martin-Santamaria, Sonsoles, and Peri, Francesco
- Subjects
lipids (amino acids, peptides, and proteins) - Abstract
The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12 and 14 carbons chains are associated to higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein.\ud The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. FT-IR, NMR, and SAXS measurements suggested that the aggregation state in aqueous solution depends on fatty acid chains lengths and that this property can influence TLR4 activity in this series of compounds.
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- 2018
5. New Synthetic Molecules Active on Human Toll-like Receptor 4
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LA FERLA, BARBARA, Minotti, A, PERI, FRANCESCO, MINOTTI, ALBERTO, LA FERLA, BARBARA, Minotti, A, PERI, FRANCESCO, and MINOTTI, ALBERTO
- Abstract
TLR4 è il recettore dell’immunità innata che riconosce selettivamente LPS di batteri Gram-negativi che hanno superato le barriere fisiche ed anatomiche del nostro organismo. TLR4 risponde a LPS batterici e a diversi ligandi endogeni in associazione con la proteina MD-2 ed innesca così le risposte immunitarie e infiammatorie necessarie per combattere l’infezione. I recettori LBP e CD14 sono coinvolti nel processo di riconoscimento di LPS e nel trasferimento di LPS dagli aggregati in soluzione al complesso TLR4-MD-2. TLR4 è stato recentemente collegato a molte importanti patologie che mancano ancora di un trattamento farmacologico specifico: sepsi e shock settico, cancro, patologie da infiammazioni acute o croniche, SLA, arteriosclerosi, allergie, asma, disordini cardiovascolari, diabete. Composti in grado di bloccare l’attivazione del TLR4 (antagonisti) sono quindi dei potenziali candidati per la cura di queste patologie, mentre composti in grado di stimolare TLR4 (agonisti) possono essere usati come agenti antitumorali o come adiuvanti vaccinali. La struttura chimica del lipide A (la parte biologicamente attiva di LPS) è stata semplificata in glicolipidi sintetici basati sulla struttura del Lipide X, il precursore biosintetico del Lipide A. Diversi fra questi composti hanno dimostrato di possedere attività agonistica o antagonistica su TLR4. Degli 8 adiuvanti vaccinali attualmente approvati o in valutazione clinica, tre sono monosaccaridi derivati delle strutture parziali del Lipide A. Tuttavia, le relazioni struttura-attività ed il passaggio da antagonismo ad agonismo o viceversa per i modulatori di TLR4 monosaccaridici non sono state ancora chiarificati. Con l’obiettivo di ottenere nuovi modulatori monosaccaridi di TLR4 (agonisti o antagonisti), allo scopo di esplorare le SAR e con altresì il fine di studiare le proprietà di binding con il co-recettore di TLR4 MD-2, durante il lavoro di questa tesi di dottorato sono stati progettate e sintetizzate 9 innov, TLR4 is the innate immunity receptor which selectively recognizes LPS from the Gram-negative bacteria that eluded the physical and anatomical barriers of our organisms. TLR4 responds to bacterial LPS and to different endogenous ligands in association with the protein adaptor MD-2 and triggers the immune and inflammatory responses. The receptors LBP and CD14 are involved in the LPS recognition process and in the transfer of LPS from aggregates in solution to TLR4-MD-2 complex . TLR4 has recently been related to many important pathologies still lacking specific pharmacological treatment: from diseases caused by bacterial infection such as sepsis and septic shock, to cancer and acute or chronic inflammatory diseases, atherosclerosis, allergies, asthma, cardiovascular disorder, diabetes. Compounds able to block TLR4 activation (antagonists) are drug candidates against these pathologies, compounds active in stimulating TLR4 (agonists) may be used as antitumoral agents or vaccine adjuvants. The chemical structure of lipid A (the biologically active part of LPS) has been simplified into synthetic glycolipids resembling lipid X, a biosynthetic precursor of lipid A. These compounds retained part of the agonist or antagonist activity on TLR4. Of the 8 vaccine adjuvants currently approved or in clinical evaluation, 3 are monosaccharide derivatives of Lipid A partial structures. However, SAR and the switch from agonism to antagonism for monosaccharide TLR4 modulators have not been completely clarified yet, nor their activities have been clearly rationalized with respect to MD-2 binding. With the aim of obtaining new monosaccharide-based TLR4 modulators (antagonists or agonists), to explore their SAR and to study their MD-2 binding properties, during this PhD thesis 9 new monosaccharide molecular simplifications of Lipid A have been projected and synthesized: FP7, FP11, FP111, AM158, AM173, AMX1, AM246248-d1, AM246248-d2 and AM241. This series of molecules has been projected by
- Published
- 2018
6. Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor 4 Antagonist Activity of a Synthetic Glycolipid
- Author
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Peri, F, Facchini, F, Coelho, H, Sestito, S, Delgado, S, Minotti, A, Andreu, D, Jiménez-Barbero, J, Peri, Francesco, Facchini, Fabio Alessandro, Coelho, Helena, Sestito, Stefania Enza, Delgado, Sandra, Minotti, Alberto, Andreu, David, Jiménez-Barbero, Jesús, Peri, F, Facchini, F, Coelho, H, Sestito, S, Delgado, S, Minotti, A, Andreu, D, Jiménez-Barbero, J, Peri, Francesco, Facchini, Fabio Alessandro, Coelho, Helena, Sestito, Stefania Enza, Delgado, Sandra, Minotti, Alberto, Andreu, David, and Jiménez-Barbero, Jesús
- Abstract
This study examines the effect of co-administration of antimicrobial peptides and the synthetic glycolipid FP7, which is active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two lipopolysaccharide (LPS)-neutralizing peptides (a cecropin A–melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, because it also occurs if cells are stimulated by the plant lectin phytohemagglutinin, a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on the LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of the TLR4 response.
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- 2018
7. Structure–Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists
- Author
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Facchini, Fabio A., primary, Zaffaroni, Lenny, additional, Minotti, Alberto, additional, Rapisarda, Silvia, additional, Calabrese, Valentina, additional, Forcella, Matilde, additional, Fusi, Paola, additional, Airoldi, Cristina, additional, Ciaramelli, Carlotta, additional, Billod, Jean-Marc, additional, Schromm, Andra B., additional, Braun, Harald, additional, Palmer, Charys, additional, Beyaert, Rudi, additional, Lapenta, Fabio, additional, Jerala, Roman, additional, Pirianov, Grisha, additional, Martin-Santamaria, Sonsoles, additional, and Peri, Francesco, additional
- Published
- 2018
- Full Text
- View/download PDF
8. Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor 4 Antagonist Activity of a Synthetic Glycolipid
- Author
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Facchini, Fabio A., primary, Coelho, Helena, additional, Sestito, Stefania E., additional, Delgado, Sandra, additional, Minotti, Alberto, additional, Andreu, David, additional, Jiménez-Barbero, Jesús, additional, and Peri, Francesco, additional
- Published
- 2018
- Full Text
- View/download PDF
9. Dye-sensitized photocatalytic hydrogen production: Distinct activity in a glucose derivative of a phenothiazine dye
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Manfredi, N, Cecconi, B, Calabrese, V, Minotti, A, Peri, F, Ruffo, R, Monai, M, Romero Ocaña, I, Montini, T, Fornasiero, P, Abbotto, A, MANFREDI, NORBERTO, CECCONI, BIANCA, CALABRESE, VALENTINA, MINOTTI, ALBERTO, PERI, FRANCESCO, RUFFO, RICCARDO, ABBOTTO, ALESSANDRO, Manfredi, N, Cecconi, B, Calabrese, V, Minotti, A, Peri, F, Ruffo, R, Monai, M, Romero Ocaña, I, Montini, T, Fornasiero, P, Abbotto, A, MANFREDI, NORBERTO, CECCONI, BIANCA, CALABRESE, VALENTINA, MINOTTI, ALBERTO, PERI, FRANCESCO, RUFFO, RICCARDO, and ABBOTTO, ALESSANDRO
- Abstract
A thiophene-based donor-acceptor phenothiazine dye has been functionalized with a peripheral glucose unit (PTZ-GLU) to bust its affinity to water and enhance dye-sensitized photogeneration of hydrogen. Compared to the corresponding alkyl derivative (PTZ-ALK), as well as the common hydrophilic triethylene glycol substitution (PTZ-TEG), the sugar derivative shows a lower contact angle; PTZ-GLU performed twice more efficient than PTZ-TEG in the photogeneration of hydrogen in terms of evolved gas and turnover number.
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- 2016
10. Structure–Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists
- Author
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Facchini, Fabio A., Zaffaroni, Lenny, Minotti, Alberto, Rapisarda, Silvia, Calabrese, Valentina, Forcella, Matilde, Fusi, Paola, Airoldi, Cristina, Ciaramelli, Carlotta, Billod, Jean-Marc, Schromm, Andra B., Braun, Harald, Palmer, Charys, Beyaert, Rudi, Lapenta, Fabio, Jerala, Roman, Pirianov, Grisha, Martin-Santamaria, Sonsoles, and Peri, Francesco
- Subjects
3. Good health - Abstract
Journal of medicinal chemistry 61(7), 2895 - 2909 (2018). doi:10.1021/acs.jmedchem.7b01803, The structure–activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds., Published by ACS, Washington, DC
11. Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity
- Author
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Nicole Gotri, Fabio A. Facchini, Alberto Minotti, Guanbo Wang, Grisha Pirianov, Marco De Andrea, Miguel A. Valvano, Alessio Romerio, Francesco Peri, Rebecca J. Ingram, Alejandra Matamoros-Recio, Charys Palmer, Sonsoles Martín-Santamaría, Andrea Luraghi, Andrea Iannucci, European Commission, Ministero dell'Istruzione, dell'Università e della Ricerca, Ministerio de Ciencia e Innovación (España), Facchini, Fabio A., Minotti, Alberto, Luraghi, Andrea, Matamoros-Recio, Alejandra, Iannucci, Andrea, Wang, Guanbo, Ingram, Rebecca, Martín-Santamaría, Sonsoles, Pirianov, Grisha, De Andrea, Marco, Valvano, Miguel A., Peri, Francesco, Facchini, F, Minotti, A, Luraghi, A, Romerio, A, Gotri, N, Matamoros-Recio, A, Iannucci, A, Palmer, C, Wang, G, Ingram, R, Martin-Santamaria, S, Pirianov, G, De Andrea, M, Valvano, M, Peri, F, Facchini, Fabio A. [0000-0002-4339-5845], Minotti, Alberto [0000-0002-0443-6472], Luraghi, Andrea [0000-0002-9452-7561], Matamoros-Recio, Alejandra [0000-0003-1563-9408], Iannucci, Andrea [0000-0001-5194-8959], Wang, Guanbo [0000-0001-8210-8805], Ingram, Rebecca [0000-0003-1832-2457], Martín-Santamaría, Sonsoles [0000-0002-7679-0155], Pirianov, Grisha [0000-0002-6480-7765], De Andrea, Marco [0000-0002-3188-5783], Valvano, Miguel A. [0000-0001-8229-3641], and Peri, Francesco [0000-0002-3417-8224]
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Macrophage ,Inflammasomes ,medicine.medical_treatment ,Monophosphoryl Lipid A ,Glycolipid ,Article ,Inflammasome ,Lipid A ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Adjuvants, Immunologic ,SDG 3 - Good Health and Well-being ,In vivo ,NLR Family, Pyrin Domain-Containing 3 Protein ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,Glucosamine ,0303 health sciences ,Animal ,Chemistry ,Macrophages ,Pattern recognition receptor ,3. Good health ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Adaptor Proteins, Vesicular Transport ,Mechanism of action ,Biochemistry ,Myeloid Differentiation Factor 88 ,Molecular Medicine ,Female ,Glycolipids ,medicine.symptom ,Adjuvant ,Human ,Interleukin-1 ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
12 p.-7 fig.-1 schem.-1 graph. abst., Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA., The support from European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860325 (www.BactiVax.eu), Italian Ministry grant PRIN 2017, no. 2017E44A9P (BacHounds:Supramolecular nanostructures for bacteria detection), and the Spanish Ministry for Science and Innovation (grants CTQ2017-88353-R and PRE2018-086249) is acknowledged.
- Published
- 2021
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