tetano
Editor, Senior Moderator
Nat Commun
. 2026 Apr 4.
doi: 10.1038/s41467-026-71436-6. Online ahead of print.
Next-generation inhibitors of SARS-CoV-2 M[SUP]pro[/SUP] overcome the deficiencies of Paxlovid
Gan Luo[SUP] #[/SUP][SUP] 1 [/SUP], Gang Wang[SUP] #[/SUP][SUP] 1 [/SUP], Chongbing Liao[SUP] #[/SUP][SUP] 1 [/SUP], Baisen Zhong[SUP] 1 [/SUP], Lianfeng Fan[SUP] 1 [/SUP], Jue Zhang[SUP] 1 [/SUP], Jie Rao[SUP] 1 [/SUP], Junjie Zhang[SUP] 1 [/SUP], Ziqiao Wang[SUP] 1 [/SUP], Man Luo[SUP] 1 [/SUP], Yan Yan[SUP] 1 [/SUP], Lu Lu[SUP] 1 [/SUP], Wei Xu[SUP] 2 [/SUP], Fan Wu[SUP] 3 [/SUP], Xihui Gao[SUP] 4 [/SUP], Wuyuan Lu[SUP] 5 [/SUP]
Affiliations
It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (M[SUP]pro[/SUP]) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design iso-quinoline-containing inhibitors with high affinity for M[SUP]pro[/SUP] and its nirmatrelvir-resistant E166X mutants. Further optimization at P4 cultivates distinctive peptidomimetic inhibitors with drastically improved pharmacokinetic properties and significantly enhanced antiviral efficacy independent of ritonavir. Two such inhibitors, FD3-32 and FD3-36, also potent against SARS-CoV-1 and MERS-CoV M[SUP]pro[/SUP], are more effective as a monotherapy regimen than Paxlovid in reducing viral loads in vivo and protecting infected male mice from acute lung injury. Here, we report the discovery of next-generation SARS-CoV-2 M[SUP]pro[/SUP] inhibitors that overcome the deficiencies of Paxlovid, promising efficacious antivirals critical for mitigating the current and future pandemics of coronaviruses.
. 2026 Apr 4.
doi: 10.1038/s41467-026-71436-6. Online ahead of print.
Next-generation inhibitors of SARS-CoV-2 M[SUP]pro[/SUP] overcome the deficiencies of Paxlovid
Gan Luo[SUP] #[/SUP][SUP] 1 [/SUP], Gang Wang[SUP] #[/SUP][SUP] 1 [/SUP], Chongbing Liao[SUP] #[/SUP][SUP] 1 [/SUP], Baisen Zhong[SUP] 1 [/SUP], Lianfeng Fan[SUP] 1 [/SUP], Jue Zhang[SUP] 1 [/SUP], Jie Rao[SUP] 1 [/SUP], Junjie Zhang[SUP] 1 [/SUP], Ziqiao Wang[SUP] 1 [/SUP], Man Luo[SUP] 1 [/SUP], Yan Yan[SUP] 1 [/SUP], Lu Lu[SUP] 1 [/SUP], Wei Xu[SUP] 2 [/SUP], Fan Wu[SUP] 3 [/SUP], Xihui Gao[SUP] 4 [/SUP], Wuyuan Lu[SUP] 5 [/SUP]
Affiliations
- PMID: 41935038
- DOI: 10.1038/s41467-026-71436-6
It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (M[SUP]pro[/SUP]) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design iso-quinoline-containing inhibitors with high affinity for M[SUP]pro[/SUP] and its nirmatrelvir-resistant E166X mutants. Further optimization at P4 cultivates distinctive peptidomimetic inhibitors with drastically improved pharmacokinetic properties and significantly enhanced antiviral efficacy independent of ritonavir. Two such inhibitors, FD3-32 and FD3-36, also potent against SARS-CoV-1 and MERS-CoV M[SUP]pro[/SUP], are more effective as a monotherapy regimen than Paxlovid in reducing viral loads in vivo and protecting infected male mice from acute lung injury. Here, we report the discovery of next-generation SARS-CoV-2 M[SUP]pro[/SUP] inhibitors that overcome the deficiencies of Paxlovid, promising efficacious antivirals critical for mitigating the current and future pandemics of coronaviruses.