Next-generation inhibitors of SARS-CoV-2 Mpro overcome the deficiencies of Paxlovid - PubMed
6 hours ago
- #SARS-CoV-2
- #Antiviral Inhibitors
- #Drug Development
- Next-generation SARS-CoV-2 Mpro inhibitors overcome deficiencies of Paxlovid, addressing drug resistance from E166X mutations and pharmacokinetic limits.
- Design replaces traditional γ-lactam with iso-quinoline P1 moiety, creating inhibitors effective against nirmatrelvir-resistant E166X mutants.
- Optimization at P4 yields peptidomimetic inhibitors with improved pharmacokinetics and enhanced antiviral efficacy without ritonavir.
- Inhibitors FD3-32 and FD3-36 show potent activity against SARS-CoV-1 and MERS-CoV Mpro.
- As monotherapy, FD3-32 and FD3-36 outperform Paxlovid in reducing viral loads and protecting male mice from acute lung injury in vivo.