Identification of strategies for the eradication of chronic viral infections

Our group has had a long-standing interest in the identification of strategies for the eradication of viral chronic infections.  After having provided several important contributions to the discovery of the successful anti-HCV drugs, we are now focusing our effort on the identification of viral or cellular factors that could be targeted in order to achieve a cure for chronic hepatitis B, and on studying the mechanisms of establishment and maintenance of the HIV “silent” reservoir, which currently represents the main obstacle to the eradication of HIV infection.

Towards a cure for chronic hepatitis B

Chronic hepatits B is recognized as one of the most 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 hardly achieved and the virus may persist in the liver of treated patients for their lifetime. The stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, is believed to be the main reason for life-long HBV persistence. Currently, drugs approved for the treatment of chronic hepatitis B include formulations of alpha-IFN and nucleos(t)ide analogs that inhibit 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, nucleos(t)ide analogs are well tolerated and potently suppress HBV replication in the majority of treated patients. However, these drugs rarely lead to permanent suppression of HBV. Life-long nucleos(t)ide analog 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”).

In the context of the CurB collaborative network, we are pursuing a number of strategies aimed at targeting different steps in viral life-cycle. These include the identification of inhibitors of HBV capsid assembly as well as the development of peptide nucleic acids that could selectively be taken up by hepatocytes and interfere with HBV gene expression. Moreover, HBV genomes containing reporter/selectable genes are being developed that could be exploited toward the identification of novel strategies to interfere with the HBV life-cycle.

Projects

  • Discovery of new drug mechanisms for the cure of chronic hepatitis B: targeting HBV with PROTAC capsid degraders
  • Discovery and development of novel pan-coronavirus antivirals against current and future pandemics

Team

Nome / NameRuolo / RoleEmail
Matteo ContiLaboratory Technicianconti@ingm.org
Francesca De MarcoMS Studentdemarco@ingm.org
Lorena DonniciSr Laboratory Techniciandonnici@ingm.org
Marika Longo MinnoloMS Studentlongo@ingm.org
Alessandro Lucini PaioniMS Studentlucinipaioni@ingm.org
Silvia MarchesePre Doctoral Fellowmarchese@ingm.org

Publications

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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