An orally available M^pro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron

Area of Science:

• Virology
• Medicinal Chemistry
• Drug Discovery

Background:

• Emerging SARS-CoV-2 variants necessitate the development of novel antiviral therapies.
• The SARS-CoV-2 main protease (Mpro) is a conserved and critical target for antiviral intervention.

Purpose of the Study:

• To identify and characterize potent Mpro inhibitors for treating SARS-CoV-2 infections.
• To evaluate the efficacy of a lead compound, Y180, against SARS-CoV-2 and its variants.

Main Methods:

• Synthesis of α-ketoamide-containing Mpro inhibitors utilizing the Ugi four-component reaction.
• In vitro enzymatic assays to determine IC50 values against SARS-CoV-2 Mpro.
• In vitro and in vivo efficacy studies in cell cultures and animal models infected with SARS-CoV-2 variants.
• Pharmacokinetic studies to assess oral bioavailability.

Main Results:

• The compound Y180 exhibited potent inhibition of SARS-CoV-2 Mpro with an IC50 of 8.1 nM.
• Y180 demonstrated broad-spectrum antiviral activity against wild-type SARS-CoV-2 and variants (Alpha, Kappa, Theta, Omicron) with nanomolar EC50 values.
• Oral administration of Y180 showed excellent bioavailability in multiple animal species and significantly reduced viral load and tissue damage in infected mice.
• Therapeutic treatment with Y180 improved survival in a lethal SARS-CoV-2 infection model.

Conclusions:

• Y180 is a potent, orally bioavailable Mpro inhibitor with broad-spectrum activity against SARS-CoV-2 and its variants.
• Y180 represents a promising lead compound for the development of an oral antiviral medication against COVID-19.
• Further clinical development of Y180 is warranted for treating SARS-CoV-2 infections.