Novel therapeutic strategies for the treatment and cure of acute and chronic viral infections
Our group has had a long-standing interest in the identification of strategies for the cure of chronic and acute viral infections. After having provided several important contributions to the discovery of the successful anti-HCV drugs, we are now focusing our effort on i) finding achieve a cure for chronic hepatitis B, and on ii) the identification of novel agents active against SARS-CoV-2 and emerging SARS-like coronaviruses.
Towards a cure for chronic hepatitis B
Chronic hepatits B is a common causes of liver cirrhosis and hepatocellular carcinoma worldwide, leading to hundreds of thousand deaths every year. Treatment of chronic hepatitis B virus (HBV) infection with antiviral therapy has led to a significant reduction in mortality related to chronic hepatitis B. However, unlike in the case for HCV, a virological cure is virtually never achieved, as the viral genome persists in the in the nuclei of infected hepatocytes for their lifetime. The stability of the HBV genome, which forms a stable episome called covalently closed circular DNA (cccDNA), is in fact believed to be the main reason for life-long HBV persistence. Currently, drugs approved for the treatment of chronic hepatitis B include formulations of α-IFN and nucleos(t)ide analogs that inhibit the HBV DNA polymerase. IFN-based treatment is effective in achieving a sustained virological response in only a fraction of patients and is associated with severe side-effects. Conversely, nucleotide analogues are well tolerated and potently suppress HBV replication in most treated patients. However, these drugs rarely lead to permanent suppression of HBV. Life-long nucleotide analogue treatment is required to continuously suppress HBV replication, which may be associated with significant cost burden, long-term drug-associated toxicity and a residual risk of developing HCC. There is, therefore, a pressing need for the discovery of therapeutic strategies effective in clearing HBV cccDNA (“complete cure”), or at least achieving stable suppression of gene expression from the cccDNA (“functional cure”).
Together with our collaborators, we are pursuing a number of strategies aimed at targeting different steps in viral life-cycle. These include the identification of novel HBV capsid assembly inhibitors/modulators (CAMs) as well as small-molecule entry inhibitors active against HBV and HDV.
Discovery of novel agents active against current and future SARS-like coronaviruses
Over the last 20 years coronaviruses (CoVs) such as SARS-CoV, MERS-CoV and, more recently, SARS-CoV-2 (the ethological agent of COVID-19 disease) have recurrently emerged from animal reservoirs, causing outbreaks of severe respiratory syndromes in humans. COVID-19 represents the worst pandemic in a hundred years, having triggered thus far about 100 million confirmed cases and more than 6 million deaths. Throughout 2022, the scientific community has been ramping-up efforts to identify COVID-19 treatments and preventives. While several novel vaccines and monoclonal antibodies have reached the market at an unprecedented speed, only a very few small molecule direct-acting antivirals (DAAs) have been approved for use in patients at risk of developing severe disease. In order to strengthen our pandemic preparadness by expanding the armamentarium of available antiviral drugs, we aim at the identification of small-molecule antivirals broadly active against SARS-CoVs and related beta-coronaviruses.
Projects
- Identification of novel HBV capsid assembly inhibitors/modulators (CAMs) and HBV/HDV entry inhibitors.
- Investigating of Hepatitis B protein “x” (HBx) as a novel therapeutic target for Chronic Hepatitis B.
- Study of the Epigenetic Modifications Induced by HBV on the Host Cell Genome: Implications for Therapy of Chronic Hepatitis B
- Development of Novel In Vitro Models for Chronic HBV and HDV Infections and Their Pharmacological Cure.
- Discovery and development of novel pan-coronavirus antivirals against current and future pandemics.
- CRISPR-Cas9 Screens to Identify Host Targets for Antiviral Therapy.
Team
| Nome / Name | Ruolo / Role | |
|---|---|---|
| Alice Andrei | Pre-doctoral Fellow | andrei@ingm.org |
| Lorena Donnici | Sr Laboratory Technician | donnici@ingm.org |
| Marika Longo Minnolo | PhD Student | longo@ingm.org |
| Silvia Marchese | PhD Student | marchese@ingm.org |
| Margherita Mosiello | Pre-doctoral Fellow | mosiello@ingm.org |
| Riccardo Nodari | Research Scientist | nodari@ingm.org |
| Illaria Tognoli | MS Thesis Student | tognoli@ingm.org |
Publications
Antibody-independent protection against heterologous SARS-CoV-2 challenge conferred by prior infection or vaccination
Fumagalli V, Ravà M, Marotta D, Di Lucia P, Bono E, Giustini L, De Leo F, Casalgrandi M, Monteleone E, Mouro V, Malpighi C, Perucchini C, Grillo M, De Palma S, Donnici L, Marchese S, Conti M, Muramatsu H, Perlman S, Pardi N, Kuka M, De Francesco E, Bianchi M, Guidotti L, Iannacone M
Nat Immunol (2024)
Tracking the immune response profiles elicited by the BNT162b2 vaccine in COVID-19 unexperienced and experienced individuals.
Galeota E, Bevilacqua V, Gobbini A, Gruarin P, Bombaci M, Pesce E, Favalli A, Lombardi A, Vincenti F, Ongaro J, Fabbris T, Curti S, Martinovic M, Toccafondi M, Lorenzo M, Critelli A, Clemente F, Crosti M, Sarnicola ML, Martinelli M, La Sala L, Espadas A, Donnici L, Borghi MO, De Feo T, De Francesco R, Prati D, Meroni PL, Notarbartolo S, Geginat J, Gori A, Bandera A, Abrignani S, Grifantini R.
Clin Immunol. 2024 Feb 28;261:110164.
Isolation and Characterization of Neutralizing Monoclonal Antibodies from a Large Panel of Murine Antibodies against RBD of the SARS-CoV-2 Spike Protein.
D’Acunto E, Muzi A, Marchese S, Donnici L, Chiarini V, Bucci F, Pavoni E, Ferrara FF, Cappelletti M, Arriga R, Serrao SM, Peluzzi V, Principato E, Compagnone M, Pinto E, Luberto L, Stoppoloni D, Lahm A, Groß R, Seidel A, Wettstein L, Münch J, Goodhead A, Parisot J, De Francesco R, Ciliberto G, Marra E, Aurisicchio L, Roscilli G.
Antibodies (Basel). 2024 Jan 5;13(1):5.
Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses.
Mazzarella L, Santoro F, Ravasio R, Fumagalli V, Massa PE, Rodighiero S, Gavilán E, Romanenghi M, Duso BA, Bonetti E, Manganaro L, Pallavi R, Trastulli D, Pallavicini I, Gentile C, Monzani S, Leonardi T, Pasqualato S, Buttinelli G, Di Martino A, Fedele G, Schiavoni I, Stefanelli P, Meroni G, de Francesco R, Steinkuhler C, Fossati G, Iannacone M, Minucci S, Pelicci PG.
Sci Signal. 2023 Dec 19;16(816):eade0326.
Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses.
Fumagalli V, Di Lucia P, Ravà M, Marotta D, Bono E, Grassi S, Donnici L, Cannalire R, Stefanelli I, Ferraro A, Esposito F, Pariani E, Inverso D, Montesano C, Delbue S, Perlman S, Tramontano E, De Francesco R, Summa V, Guidotti LG, Iannacone M.
EMBO Mol Med. 2023 Mar 22:e17580.
Interferon-inducible phospholipids govern IFITM3-dependent endosomal antiviral immunity.
Unali G, Crivicich G, Pagani I, Abou-Alezz M, Folchini F, Valeri E, Matafora V, Reisz JA, Giordano AMS, Cuccovillo I, Butta GM, Donnici L, D’Alessandro A, De Francesco R, Manganaro L, Cittaro D, Merelli I, Petrillo C, Bachi A, Vicenzi E, Kajaste-Rudnitski A. I
EMBO J. 2023 Mar 27:e112234.
Mapping of functional SARS-CoV-2 receptors in human lungs establishes differences in variant binding and SLC1A5 as a viral entry modulator of hACE2.
Miluzio A, Cuomo A, Cordiglieri C, Donnici L, Pesce E, Bombaci M, Conti M, Fasciani A, Terracciano L, Manganaro L, Toccafondi M, Scagliola A, Oliveto S, Ricciardi S, Grifantini R, De Francesco R, Abrignani S, Manfrini N, Biffo S.
EBioMedicine. 2023 Jan;87:104390.
B cell analyses after SARS-CoV-2 mRNA third vaccination reveals a hybrid immunity like antibody response.
Andreano E, Paciello I, Pierleoni G, Piccini G, Abbiento V, Antonelli G, Pileri P, Manganaro N, Pantano E, Maccari G, Marchese S, Donnici L, Benincasa L, Giglioli G, Leonardi M, De Santi C, Fabbiani M, Rancan I, Tumbarello M, Montagnani F, Sala C, Medini D, De Francesco R, Montomoli E, Rappuoli R.
Nat Commun. 2023 Jan 4;14(1):53.
Memory CD8+ T cell diversity and B cell responses correlate with protection against SARS-CoV-2 following mRNA vaccination.
Brasu N, Elia I, Russo V, Montacchiesi G, Stabile SA, De Intinis C, Fesi F, Gizzi K, Macagno M, Montone M, Mussolin B, Grifoni A, Faravelli S, Marchese S, Forneris F, De Francesco R, Sette A, Barnaba V, Sottile A, Sapino A, Pace L.
Nat Immunol. 2022 Oct;23(10):1445-1456.
Discovery and antiviral profile of new sulfamoylbenzamide derivatives as HBV capsid assembly modulators.
Ivanova Bencheva L, Donnici L, Ferrante L, Prandi A, Sinisi R, De Matteo M, Randazzo P, Conti M, Di Lucia P, Bono E, Giustini L, Vittoria Orsale M, Patsilinakos A, Monteagudo E, Iannacone M, Summa V, Guidotti LG, De Francesco R, Di Fabio R.
Bioorg Med Chem Lett. 2022 Oct 1;73:128904.
Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees.
Andreano E, Paciello I, Marchese S, Donnici L, Pierleoni G, Piccini G, Manganaro N, Pantano E, Abbiento V, Pileri P, Benincasa L, Giglioli G, Leonardi M, Maes P, De Santi C, Sala C, Montomoli E, De Francesco R, Rappuoli R.
Nat Commun. 2022 Jun 13;13(1):3375.
Structural insights of a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody.
Torres JL, Ozorowski G, Andreano E, Liu H, Copps J, Piccini G, Donnici L, Conti M, Planchais C, Planas D, Manganaro N, Pantano E, Paciello I, Pileri P, Bruel T, Montomoli E, Mouquet H, Schwartz O, Sala C, De Francesco R, Wilson IA, Rappuoli R, Ward AB.
Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2120976119.
Heterogeneity of Latency Establishment in the Different Human CD4+ T Cell Subsets Stimulated with IL-15.
Butta GM, Bozzi G, Gallo G, Copaloni G, Cordiglieri C, Crosti M, Mancino M, Prati D, Simon V, Gori A, Bandera A, De Francesco R, Manganaro L.
J Virol. 2022 May 25;96(10):e0037922.
DNA-Vaccine-Induced Immune Response Correlates with Lower Viral SARS-CoV-2 Titers in a Ferret Model.
Compagnone M, Pinto E, Salvatori E, Lione L, Conforti A, Marchese S, Ravà M, Ryan K, Hall Y, Rayner E, Salguero FJ, Paterson J, Iannacone M, De Francesco R, Aurisicchio L, Palombo F.
Vaccines (Basel). 2022 Jul 25;10(8):1178.
Immunosuppressant Treatment in Rheumatic Musculoskeletal Diseases Does Not Inhibit Elicitation of Humoral Response to SARS-CoV-2 Infection and Preserves Effector Immune Cell Populations.
Favalli A, Favalli EG, Gobbini A, Zagato E, Bombaci M, Maioli G, Pesce E, Donnici L, Gruarin P, Biggioggero M, Curti S, Manganaro L, Marchisio E, Bevilacqua V, Martinovic M, Fabbris T, Sarnicola ML, Crosti M, Marongiu L, Granucci F, Notarbartolo S, Bandera A, Gori A, De Francesco R, Abrignani S, Caporali R, Grifantini R.
Front Immunol. 2022 Jun 10;13:873195.
Synthetic carbohydrate-binding agents neutralize SARS-CoV-2 by inhibiting binding of the spike protein to ACE2.
Francesconi O, Donnici L, Fragai M, Pesce E, Bombaci M, Fasciani A, Manganaro L, Conti M, Grifantini R, De Francesco R, Nativi C, Roelens S.
iScience. 2022 May 20;25(5):104239.
Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response.
Pesce E, Manfrini N, Cordiglieri C, Santi S, Bandera A, Gobbini A, Gruarin P, Favalli A, Bombaci M, Cuomo A, Collino F, Cricrì G, Ungaro R, Lombardi A, Mangioni D, Muscatello A, Aliberti S, Blasi F, Gori A, Abrignani S, De Francesco R, Biffo S, Grifantini R.
Front Immunol. 2022 Jan 17;12:785941.
Anti-spike antibodies and neutralising antibody activity in people living with HIV vaccinated with COVID-19 mRNA-1273 vaccine: a prospective single-centre cohort study.
Lombardi A, Butta GM, Donnici L, Bozzi G, Oggioni M, Bono P, Matera M, Consonni D, Ludovisi S, Muscatello A, Ceriotti F, Conti M, Scaglioni S, Gallo G, Scarpa E, Letko M, Abrignani S, Grifantini R, De Francesco R, Gori A, Manganaro L, Bandera A.
Lancet Reg Health Eur. 2022 Feb;13:100287.
Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.
Fumagalli V, Ravà M, Marotta D, Di Lucia P, Laura C, Sala E, Grillo M, Bono E, Giustini L, Perucchini C, Mainetti M, Sessa A, Garcia-Manteiga JM, Donnici L, Manganaro L, Delbue S, Broccoli V, De Francesco R, D’Adamo P, Kuka M, Guidotti LG, Iannacone M.
Sci Immunol. 2022 Jan 28;7(67):eabl9929.
DNA aptamers masking angiotensin converting enzyme 2 as an innovative way to treat SARS-CoV-2 pandemic.
Villa A, Brunialti E, Dellavedova J, Meda C, Rebecchi M, Conti M, Donnici L, De Francesco R, Reggiani A, Lionetti V, Ciana P.
Pharmacol Res. 2022 Jan;175:105982.
COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models.
Conforti A, Marra E, Palombo F, Roscilli G, Ravà M, Fumagalli V, Muzi A, Maffei M, Luberto L, Lione L, Salvatori E, Compagnone M, Pinto E, Pavoni E, Bucci F, Vitagliano G, Stoppoloni D, Pacello ML, Cappelletti M, Ferrara FF, D’Acunto E, Chiarini V, Arriga R, Nyska A, Di Lucia P, Marotta D, Bono E, Giustini L, Sala E, Perucchini C, Paterson J, Ryan KA, Challis AR, Matusali G, Colavita F, Caselli G, Criscuolo E, Clementi N, Mancini N, Groß R, Seidel A, Wettstein L, Münch J, Donnici L, Conti M, De Francesco R, Kuka M, Ciliberto G, Castilletti C, Capobianchi MR, Ippolito G, Guidotti LG, Rovati L, Iannacone M, Aurisicchio L.
Mol Ther. 2022 Jan 5;30(1):311-326.
Novel interferon-sensitive genes unveiled by correlation-driven gene selection and systems biology.
Cheroni C, Manganaro L, Donnici L, Bevilacqua V, Bonnal RJP, Rossi RL, De Francesco R.
Sci Rep. 2021 Sep 10;11(1):18043.
Integrated longitudinal immunophenotypic, transcriptional and repertoire analyses delineate immune responses in COVID-19 patients.
Notarbartolo S, Ranzani V, Bandera A, Gruarin P, Bevilacqua V, Putignano AR, Gobbini A, Galeota E, Manara C, Bombaci M, Pesce E, Zagato E, Favalli A, Sarnicola ML, Curti S, Crosti M, Martinovic M, Fabbris T, Marini F, Donnici L, Lorenzo M, Mancino M, Ungaro R, Lombardi A, Mangioni D, Muscatello A, Aliberti S, Blasi F, De Feo T, Prati D, Manganaro L, Granucci F, Lanzavecchia A, De Francesco R, Gori A, Grifantini R, Abrignani S.
Sci Immunol. 2021 Aug 10;6(62):eabg5021.
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