Background
Despite widespread immunity from SARS-CoV-2 vaccination and/or past infection, safe, effective, and convenient treatments for acute infection are still needed for individuals who remain at high risk for disease progression. Moreover, the risk of another coronavirus pandemic is an ongoing threat to global health. In this context, the development of pan-coronavirus therapeutics is a critical component of pandemic preparedness to avoid a repeat of the immense public health and societal costs caused by COVID-19.
Methods
The 3-chymotrypsin like protease (3CLpro) from SARS-CoV-2 and other human and bat coronaviruses was used in enzymatic assays to assess the inhibitory activity of ALG‑097558. The antiviral activity was tested in cell-based assays with SARS-CoV-2, SARS-CoV-1, MERS-CoV and other α- and β-coronaviruses. Bioinformatics analysis was performed to assess sequence conservation in currently circulating SARS-CoV-2 strains and predict susceptibility to ALG-097558.
Results
ALG-097558 is a potent inhibitor of the SARS-CoV-2 3CLpro (Wuhan strain) with an IC50 of 0.22 nM in enzymatic assays. ALG-097558 retained strong inhibitory activity when tested against the 3CLpro derived from SARS-CoV-2 Omicron, MERS-CoV, human α- CoVs NL63 and 229E and β-CoV HKU-1 as well as 3CLpros derived from several bat CoVs with the potential to infect human cells. In cell-based experiments, ALG-097558 demonstrated pan-coronavirus activity with a narrow EC50 range of 7-40 nM against 8 different SARS-CoV-2 isolates including the Omicron subvariants BA.2, BA.5, BQ.1 and XBB1.5, as well as other human coronaviruses including SARS-CoV-1, MERS-CoV, 229E, the human β-CoV OC43 and a feline CoV. Against Omicron subvariants, ALG-097558 is 3- to 9-fold more active than nirmatrelvir (the 3CLpro inhibitor in Paxlovid™). Other 3CLpro inhibitors in clinical development such as ensitrelvir and ibuzatrelvir demonstrated greatly reduced antiviral activity against α-CoVs. Bioinformatics analysis predicts that ALG-097558 will retain antiviral activity against currently circulating SARS-CoV-2 strains.
Conclusions
ALG-097558 demonstrates potent, pan-coronaviral activity in preclinical experiments and is uniquely positioned as a treatment option for SARS-CoV-2 infection and potential future coronavirus pandemics. After having demonstrated a favorable clinical safety and PK profile in Phase I, including ritonavir-free dosing, ALG-097558 warrants further evaluation in patients with COVID-19.
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