tetano
Editor, Senior Moderator
Antiviral Res
. 2024 Jul 23:105969.
doi: 10.1016/j.antiviral.2024.105969. Online ahead of print. Highly specific SARS-CoV-2 main protease (M[SUP]pro[/SUP]) mutations against the clinical antiviral ensitrelvir selected in a safe, VSV-based system
Stefanie Rauch[SUP] 1 [/SUP], Francesco Costacurta[SUP] 1 [/SUP], Helge Schöppe[SUP] 2 [/SUP], Ju-Yi Peng[SUP] 3 [/SUP], David Bante[SUP] 4 [/SUP], Ela Emilie Erisoez[SUP] 4 [/SUP], Bernhard Sprenger[SUP] 5 [/SUP], Xi He[SUP] 3 [/SUP], Seyed Arad Moghadasi[SUP] 6 [/SUP], Laura Krismer[SUP] 1 [/SUP], Anna Sauerwein[SUP] 1 [/SUP], Anne Heberle[SUP] 1 [/SUP], Toni Rabensteiner[SUP] 1 [/SUP], Dai Wang[SUP] 3 [/SUP], Andreas Naschberger[SUP] 7 [/SUP], Theresia Dunzendorfer-Matt[SUP] 4 [/SUP], Teresa Kaserer[SUP] 2 [/SUP], Dorothee von Laer[SUP] 1 [/SUP], Emmanuel Heilmann[SUP] 8 [/SUP]
Affiliations
In the SARS-CoV-2 pandemic, the so far two most effective approved antivirals are the protease inhibitors nirmatrelvir, in combination with ritonavir (Paxlovid) and ensitrelvir (Xocova). However, antivirals and indeed all antimicrobial drugs are sooner or later challenged by resistance mutations. Studying such mutations is essential for treatment decisions and pandemic preparedness. At the same time, generating resistant viruses to assess mutants is controversial, especially with pathogens of pandemic potential like SARS-CoV-2. To circumvent gain-of-function research with non-attenuated SARS-CoV-2, a previously developed safe system based on a chimeric vesicular stomatitis virus dependent on the SARS-CoV-2 main protease (VSV-M[SUP]pro[/SUP]) was used to select mutations against ensitrelvir. Ensitrelvir is clinically especially relevant due to its single-substance formulation, avoiding drug-drug interactions by the co-formulated CYP3A4 inhibitor ritonavir in Paxlovid. By treating VSV-M[SUP]pro[/SUP] with ensitrelvir, several highly-specific resistant mutants against this inhibitor were selected, while being still fully or largely susceptible to nirmatrelvir. We then confirmed several ensitrelvir-specific mutants in gold standard enzymatic assays and SARS-CoV-2 replicons. These findings indicate that the two inhibitors can have distinct viral resistance profiles, which could determine treatment decisions.
Keywords: 3CL(pro); M(pro); Paxlovid; S-217622; SARS-CoV-2; VSV-based resistance selection; Xocova; antivirals; ensitrelvir; nirmatrelvir; nsp5; resistance.
. 2024 Jul 23:105969.
doi: 10.1016/j.antiviral.2024.105969. Online ahead of print. Highly specific SARS-CoV-2 main protease (M[SUP]pro[/SUP]) mutations against the clinical antiviral ensitrelvir selected in a safe, VSV-based system
Stefanie Rauch[SUP] 1 [/SUP], Francesco Costacurta[SUP] 1 [/SUP], Helge Schöppe[SUP] 2 [/SUP], Ju-Yi Peng[SUP] 3 [/SUP], David Bante[SUP] 4 [/SUP], Ela Emilie Erisoez[SUP] 4 [/SUP], Bernhard Sprenger[SUP] 5 [/SUP], Xi He[SUP] 3 [/SUP], Seyed Arad Moghadasi[SUP] 6 [/SUP], Laura Krismer[SUP] 1 [/SUP], Anna Sauerwein[SUP] 1 [/SUP], Anne Heberle[SUP] 1 [/SUP], Toni Rabensteiner[SUP] 1 [/SUP], Dai Wang[SUP] 3 [/SUP], Andreas Naschberger[SUP] 7 [/SUP], Theresia Dunzendorfer-Matt[SUP] 4 [/SUP], Teresa Kaserer[SUP] 2 [/SUP], Dorothee von Laer[SUP] 1 [/SUP], Emmanuel Heilmann[SUP] 8 [/SUP]
Affiliations
- PMID: 39053514
- DOI: 10.1016/j.antiviral.2024.105969
In the SARS-CoV-2 pandemic, the so far two most effective approved antivirals are the protease inhibitors nirmatrelvir, in combination with ritonavir (Paxlovid) and ensitrelvir (Xocova). However, antivirals and indeed all antimicrobial drugs are sooner or later challenged by resistance mutations. Studying such mutations is essential for treatment decisions and pandemic preparedness. At the same time, generating resistant viruses to assess mutants is controversial, especially with pathogens of pandemic potential like SARS-CoV-2. To circumvent gain-of-function research with non-attenuated SARS-CoV-2, a previously developed safe system based on a chimeric vesicular stomatitis virus dependent on the SARS-CoV-2 main protease (VSV-M[SUP]pro[/SUP]) was used to select mutations against ensitrelvir. Ensitrelvir is clinically especially relevant due to its single-substance formulation, avoiding drug-drug interactions by the co-formulated CYP3A4 inhibitor ritonavir in Paxlovid. By treating VSV-M[SUP]pro[/SUP] with ensitrelvir, several highly-specific resistant mutants against this inhibitor were selected, while being still fully or largely susceptible to nirmatrelvir. We then confirmed several ensitrelvir-specific mutants in gold standard enzymatic assays and SARS-CoV-2 replicons. These findings indicate that the two inhibitors can have distinct viral resistance profiles, which could determine treatment decisions.
Keywords: 3CL(pro); M(pro); Paxlovid; S-217622; SARS-CoV-2; VSV-based resistance selection; Xocova; antivirals; ensitrelvir; nirmatrelvir; nsp5; resistance.