The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread around the world and caused the 2019–2020 pandemic. Even though successful vaccination programs to combat COVID-19 are available worldwide, little has been accomplished in the development of antivirals to treat the disease. The disparity in COVID-19 vaccination coverage, vaccine resistance, the emergence of several SARS-CoV-2 variants, and the increased transmission ability emphasize the importance of developing antiviral drugs to treat SARS-CoV-2 infections.1 The development of new antiviral agents is, therefore, of utmost importance. The SARS-CoV-2 non-structural protein 13 (nsp13) has been identified as a promising drug target for the development of antivirals due to its crucial role in viral replication. The CoVs nsp13 is a multidomain enzyme that targets the natural nucleotides and deoxynucleotides as substrates when performing its adenosine triphosphatase (ATPase) activity, utilizing the energy of nucleotide triphosphate hydrolysis to unwind DNA or RNA. Moreover, nsp13 is the most conserved non-structural protein within the coronavirus family.2 Several compounds have been reported to inhibit SARS-CoV-1 nsp13 and, very recently, also SARS-CoV-2 nsp13 has been actively explored as drug target, with some reports describing small molecules as inhibitors of SARS-CoV-2 nsp13. Among them, aryl diketo acids (DKAs), have been reported as inhibitors of SARS-CoV-2 nsp13.3 On the other hand, the DKA chain suffers from several limits related to the pharmacokinetic and pharmacodynamic profiles. Therefore, to overcome the limits of the DKA moiety, a variety of compounds were developed by transferring the DKA chain to scaffolds characterized by improved druglike qualities. Therefore, we carried out a semi-random screening on our in-house library of non-DKA derivatives, identifying a promising hit compound as micromolar nsp13 inhibitor. We synthesized a set of derivatives structurally correlated with the hit, obtaining a new series of dual inhibitors of both the SARS-CoV-2 nsp13-associated activities. The data coming from the biological assays will be shown and discussed.
New nitrogen based derivatives as SARS-CoV-2 nsp13 inhibitors / Albano, A.; Madia, V. N.; Ruggieri, G.; Ialongo, D.; Patacchini, E.; Arpacioglu, M.; Messore, A.; Scipione, L.; Corona, A.; Esposito, F.; Amatore, D.; Faggioni, G.; De Santis, R.; Lista, F.; Tramontano, E.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno SCI 2024 Chemistry ELEMENTS OF FUTURE - XXVIII Congresso Nazionale della Società Chimica Italiana tenutosi a Milan).
New nitrogen based derivatives as SARS-CoV-2 nsp13 inhibitors
Albano, A.
;Madia, V. N.;Ialongo, D.;Patacchini, E.;Arpacioglu, M.;Messore, A.;Scipione, L.;Amatore, D.;Faggioni, G.;Tramontano, E.;Di Santo, R.;Costi, R.
2024
Abstract
The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread around the world and caused the 2019–2020 pandemic. Even though successful vaccination programs to combat COVID-19 are available worldwide, little has been accomplished in the development of antivirals to treat the disease. The disparity in COVID-19 vaccination coverage, vaccine resistance, the emergence of several SARS-CoV-2 variants, and the increased transmission ability emphasize the importance of developing antiviral drugs to treat SARS-CoV-2 infections.1 The development of new antiviral agents is, therefore, of utmost importance. The SARS-CoV-2 non-structural protein 13 (nsp13) has been identified as a promising drug target for the development of antivirals due to its crucial role in viral replication. The CoVs nsp13 is a multidomain enzyme that targets the natural nucleotides and deoxynucleotides as substrates when performing its adenosine triphosphatase (ATPase) activity, utilizing the energy of nucleotide triphosphate hydrolysis to unwind DNA or RNA. Moreover, nsp13 is the most conserved non-structural protein within the coronavirus family.2 Several compounds have been reported to inhibit SARS-CoV-1 nsp13 and, very recently, also SARS-CoV-2 nsp13 has been actively explored as drug target, with some reports describing small molecules as inhibitors of SARS-CoV-2 nsp13. Among them, aryl diketo acids (DKAs), have been reported as inhibitors of SARS-CoV-2 nsp13.3 On the other hand, the DKA chain suffers from several limits related to the pharmacokinetic and pharmacodynamic profiles. Therefore, to overcome the limits of the DKA moiety, a variety of compounds were developed by transferring the DKA chain to scaffolds characterized by improved druglike qualities. Therefore, we carried out a semi-random screening on our in-house library of non-DKA derivatives, identifying a promising hit compound as micromolar nsp13 inhibitor. We synthesized a set of derivatives structurally correlated with the hit, obtaining a new series of dual inhibitors of both the SARS-CoV-2 nsp13-associated activities. The data coming from the biological assays will be shown and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
