Having encountered a great pandemic worldwide caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2), we are still on the track to find a potent antiviral agent. Among those studies and results acquired so far, compounds possessing nitrogen-based heterocyclic aromatic cores such as nucleoside-like compounds (nucleoside analogues), oxadiazoles, thiadiazoles, quinolines, isoquinolines and certain polyphenolics have been demonstrated to hold a promising potential as SARS-CoV-2 inhibitors likewise in Molnupiravir and Nirmatrelvir, FDA-approved and/or emergency-use-authorization-given medicines.1 Apart from that, RNA-dependent RNA-polymerase (RdRp) is known to be an ideal target for drug development for various reasons: (1) the absence of its counterpart in human cells, (2) holding great potential against various viruses since the target is conserved, (3) the possibility of broad-spectrum antiviral activity owing to their well-conserved nature – a natural genetic barrier to drug-resistance, (4) the presence of only nucleos(t)ide analogues such as Remdesivir or orally-available counterpart namely, Molnupiravir, with several side effects and the absence of small molecule against RdRp.2 These reasons encouraged us to investigate novel nitrogen-based small molecules as RdRp inhibitors. In this sense, we carried out an extensive screening of our in-house library which was previously synthesized.3-4 A preliminary screening was performed in order to demonstrate enzymatic activity of compounds as IC50 values by using RdRp SARS-CoV-2 Primer elongation assay on PAGE. The results indicate that some of compounds tested show similar IC50 to Simeprevir, the positive control, pointing out promising enzymatic activity against RdRp in low micromolar range. Moreover, the structure activity relationship of hit is on-going. Inspired by the hit, we have synthesized some analogues of our hit, which are currently under biological evaluation. The upcoming data will be shown and discussed.
Nitrogen-based derivatives as RNA-dependent RNA polymerase inhibitors of SARS-CoV-2 / Ruggieri, G.; Madia, V. N.; Patacchini, E.; Ialongo, D.; Messore, A.; Albano, A.; Arpacioglu, M.; Malune, ; P., Esposito; Scipione, L.; Tramontano, E.; Di Santo, R.; Costi, R.. - (2024). (Intervento presentato al convegno EFMC-YMCS 2024 11th EFMC Young Medicinal Chemists' Symposium tenutosi a Rome, Italy).
Nitrogen-based derivatives as RNA-dependent RNA polymerase inhibitors of SARS-CoV-2.
Madia, V. N.;Patacchini, E.;Ialongo, D.;Messore, A.;Albano, A.;Arpacioglu, M.;Scipione, L.;Tramontano, E.;Di Santo, R.;Costi, R.
2024
Abstract
Having encountered a great pandemic worldwide caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2), we are still on the track to find a potent antiviral agent. Among those studies and results acquired so far, compounds possessing nitrogen-based heterocyclic aromatic cores such as nucleoside-like compounds (nucleoside analogues), oxadiazoles, thiadiazoles, quinolines, isoquinolines and certain polyphenolics have been demonstrated to hold a promising potential as SARS-CoV-2 inhibitors likewise in Molnupiravir and Nirmatrelvir, FDA-approved and/or emergency-use-authorization-given medicines.1 Apart from that, RNA-dependent RNA-polymerase (RdRp) is known to be an ideal target for drug development for various reasons: (1) the absence of its counterpart in human cells, (2) holding great potential against various viruses since the target is conserved, (3) the possibility of broad-spectrum antiviral activity owing to their well-conserved nature – a natural genetic barrier to drug-resistance, (4) the presence of only nucleos(t)ide analogues such as Remdesivir or orally-available counterpart namely, Molnupiravir, with several side effects and the absence of small molecule against RdRp.2 These reasons encouraged us to investigate novel nitrogen-based small molecules as RdRp inhibitors. In this sense, we carried out an extensive screening of our in-house library which was previously synthesized.3-4 A preliminary screening was performed in order to demonstrate enzymatic activity of compounds as IC50 values by using RdRp SARS-CoV-2 Primer elongation assay on PAGE. The results indicate that some of compounds tested show similar IC50 to Simeprevir, the positive control, pointing out promising enzymatic activity against RdRp in low micromolar range. Moreover, the structure activity relationship of hit is on-going. Inspired by the hit, we have synthesized some analogues of our hit, which are currently under biological evaluation. The upcoming data will be shown and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
