The diffusion of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic with unprecedent socioeconomical impact, enlightening the need of new antiviral agents able to block viral replication. The development of vaccines is essential in the containment of the diffusion of the virus, and an incredible joint effort led to a global vaccination campaign in about 1 year after the virus outbreak. However, vaccines may be less or no effective against emerging variants of SARS-CoV-2 and, also, it is still unknown how long this vaccine-induced immunity will last. Therefore, the development of antiviral drugs against SARS-CoV-2 is of pivotal importance. The SARS-CoV-2 non-structural protein 13 (nsp13) has been identified as a target for antiviral drugs thanks to its critical role in viral replication and to its high sequence conservation within the coronavirus family. Nsp13 targets the natural nucleotides and deoxynucleotides as substrates when performing its adenosine triphosphatase (ATPase) activity, utilizing the energy of nucleotide triphosphate hydrolysis to catalyze the unwinding of double-stranded DNA or RNA in a 5′ to 3′ direction. Although the roles of nsp13 in the viral lifecycle, there is a paucity of information about small molecules compounds reported in literature endowed with nsp13-inhibitory activity. Aryl diketo acids (DKAs) have been previously described as inhibitors of nsp13 of SARS-CoV-1. Basing on these literature data and thanks to our longstanding expertise in the design and synthesis of DKA derivatives, we carried out a semi-random screening on our in-house library of DKA compounds, identifying a promising hit compound as micromolar nsp13 inhibitor. We synthesized a set of indolyl DKA derivatives as structurally correlated with the identified hit, obtaining new dual SARS-CoV-2 nsp13 ATPase and helicase inhibitors, also capable of inhibiting viral replication. Mode-of-action studies revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding. The data coming from the biological assays will be shown and discussed.
Diketo acid heterocyclic derivatives as new SARS-CoV-2 nsp13 inhibitors blocking viral replication / Ialongo, D.; Madia, V. N.; Messore, A.; Patacchini, E.; Arpacioglu, M.; Tudino, V.; Scipione, L.; Corona, A.; Esposito, F.; Artico, M.; Amatore, D.; Faggioni, G.; De Santis, R.; Lista, F.; Tramontano, E.; Costi, R.; Di Santo, R.. - (2023). (Intervento presentato al convegno IX EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry tenutosi a Zagreb; Croatia.).
Diketo acid heterocyclic derivatives as new SARS-CoV-2 nsp13 inhibitors blocking viral replication.
Ialongo, D.;Madia, V. N.;Messore, A.;Patacchini, E.;Arpacioglu, M.;Tudino, V.;Scipione, L.;Costi, R.;Di Santo, R.
2023
Abstract
The diffusion of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic with unprecedent socioeconomical impact, enlightening the need of new antiviral agents able to block viral replication. The development of vaccines is essential in the containment of the diffusion of the virus, and an incredible joint effort led to a global vaccination campaign in about 1 year after the virus outbreak. However, vaccines may be less or no effective against emerging variants of SARS-CoV-2 and, also, it is still unknown how long this vaccine-induced immunity will last. Therefore, the development of antiviral drugs against SARS-CoV-2 is of pivotal importance. The SARS-CoV-2 non-structural protein 13 (nsp13) has been identified as a target for antiviral drugs thanks to its critical role in viral replication and to its high sequence conservation within the coronavirus family. Nsp13 targets the natural nucleotides and deoxynucleotides as substrates when performing its adenosine triphosphatase (ATPase) activity, utilizing the energy of nucleotide triphosphate hydrolysis to catalyze the unwinding of double-stranded DNA or RNA in a 5′ to 3′ direction. Although the roles of nsp13 in the viral lifecycle, there is a paucity of information about small molecules compounds reported in literature endowed with nsp13-inhibitory activity. Aryl diketo acids (DKAs) have been previously described as inhibitors of nsp13 of SARS-CoV-1. Basing on these literature data and thanks to our longstanding expertise in the design and synthesis of DKA derivatives, we carried out a semi-random screening on our in-house library of DKA compounds, identifying a promising hit compound as micromolar nsp13 inhibitor. We synthesized a set of indolyl DKA derivatives as structurally correlated with the identified hit, obtaining new dual SARS-CoV-2 nsp13 ATPase and helicase inhibitors, also capable of inhibiting viral replication. Mode-of-action studies revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding. 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.
