tetano
Editor, Senior Moderator
Eur J Med Chem
. 2024 Sep 16:279:116886.
doi: 10.1016/j.ejmech.2024.116886. Online ahead of print. Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease
Theodoros Rampias[SUP] 1 [/SUP], Thomas Antoniou[SUP] 2 [/SUP], Annelies Stevaert[SUP] 3 [/SUP], Lara Kravariti[SUP] 4 [/SUP], Benjamin Van Loy[SUP] 3 [/SUP], Julie Vandeput[SUP] 3 [/SUP], Jacopo Sgrignani[SUP] 5 [/SUP], Natalia Filippidou[SUP] 1 [/SUP], Patrizia Locatelli[SUP] 5 [/SUP], Martina Samiotaki[SUP] 6 [/SUP], Eleftherios Paraskevas Tzakos[SUP] 4 [/SUP], Andrea Cavalli[SUP] 5 [/SUP], Lieve Naesens[SUP] 3 [/SUP], Diamantis C Sideris[SUP] 7 [/SUP], Andreas G Tzakos[SUP] 8 [/SUP]
Affiliations
The global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) urges the development of new antiviral agents with broad coronavirus coverage. Due to its key role in viral evasion from the host innate immune response, the coronavirus Nsp15 uridine-specific endoribonuclease (EndoU) is of high interest as a drug target. Considering that the isatin scaffold is well-known for its versatile pharmacological properties, we synthesized and evaluated a series of compounds carrying an isatin core. The initial compounds were selected on the basis of in silico predictions. After biochemical assays showed moderate inhibition of SARS-CoV-2 EndoU-mediated RNA cleavage, structural analogues were rationally designed to enhance the interaction with the target. This included the incorporation of a nitrile group since this dipole can improve ADME and facilitate polar interactions with proteins and can operate as hydroxy or carboxy surrogate. A straightforward solvent free and green, microwave-assisted synthetic process was established to achieve the development of the different target compounds. The best compound exhibited inhibitory activity in enzymatic EndoU assays, and reduced the SARS-CoV-2 viral RNA load by almost 68,000-fold in the low micromolar range similarly to the established antiviral agent GS-441524.
. 2024 Sep 16:279:116886.
doi: 10.1016/j.ejmech.2024.116886. Online ahead of print. Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease
Theodoros Rampias[SUP] 1 [/SUP], Thomas Antoniou[SUP] 2 [/SUP], Annelies Stevaert[SUP] 3 [/SUP], Lara Kravariti[SUP] 4 [/SUP], Benjamin Van Loy[SUP] 3 [/SUP], Julie Vandeput[SUP] 3 [/SUP], Jacopo Sgrignani[SUP] 5 [/SUP], Natalia Filippidou[SUP] 1 [/SUP], Patrizia Locatelli[SUP] 5 [/SUP], Martina Samiotaki[SUP] 6 [/SUP], Eleftherios Paraskevas Tzakos[SUP] 4 [/SUP], Andrea Cavalli[SUP] 5 [/SUP], Lieve Naesens[SUP] 3 [/SUP], Diamantis C Sideris[SUP] 7 [/SUP], Andreas G Tzakos[SUP] 8 [/SUP]
Affiliations
- PMID: 39312834
- DOI: 10.1016/j.ejmech.2024.116886
The global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) urges the development of new antiviral agents with broad coronavirus coverage. Due to its key role in viral evasion from the host innate immune response, the coronavirus Nsp15 uridine-specific endoribonuclease (EndoU) is of high interest as a drug target. Considering that the isatin scaffold is well-known for its versatile pharmacological properties, we synthesized and evaluated a series of compounds carrying an isatin core. The initial compounds were selected on the basis of in silico predictions. After biochemical assays showed moderate inhibition of SARS-CoV-2 EndoU-mediated RNA cleavage, structural analogues were rationally designed to enhance the interaction with the target. This included the incorporation of a nitrile group since this dipole can improve ADME and facilitate polar interactions with proteins and can operate as hydroxy or carboxy surrogate. A straightforward solvent free and green, microwave-assisted synthetic process was established to achieve the development of the different target compounds. The best compound exhibited inhibitory activity in enzymatic EndoU assays, and reduced the SARS-CoV-2 viral RNA load by almost 68,000-fold in the low micromolar range similarly to the established antiviral agent GS-441524.