Clinical candidate for 3C-like protease inhibitor as a therapeutic agent for SARS-CoV-2 S-217622

In a recent study posted on bioRxiv* Preprint server, research team is a clinical candidate for a non-shared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease (3CLpro) inhibitor for the treatment of coronavirus disease S- 217622 was discovered 2019 (COVID-19 (new coronavirus infection).

To date, more than 364 confirmed COVID-19 cases have been reported worldwide, including 5.6 million deaths. The lack of treatment options to treat COVID-19 infections and associated hospitalizations requires the development of oral COVID-19 treatment options, especially for non-hospitalized patients to minimize the severity of the disease. increase.

Potential drug candidates for COVID-19 treatment are non-shared, non-peptide, small molecule inhibition that requires further optimization to achieve appropriate pharmacokinetic (PK) profiles and efficacy against SARS-CoV-2. Contains agents.

About research

In this study, we described the discovery and preclinical characteristics of S-217622, ​​the first non-peptidic, non-covalent SARS-CoV-2 3Clpro inhibitor as a clinical candidate for COVID-19 treatment.

This study utilized a structure-based drug design (SBDD) strategy that included virtual screening based on molecular docking and in-house biological screening.

Compound library. Interactions between known inhibitors have been used as the basis for investigating the pharmacophore of the binding site of 3Clpro. After docking the in-house library compounds, we applied a pharmacophore filter to each docking pose.

The evaluation of the compound with the highest score of 300 was performed by mass spectrometry using an enzyme assay. One of these compounds, compound 1, was particularly important due to its good PK profile. We have developed clinical candidate S-217622 by optimizing multiple parameters of compound 1. The cytopathic effect of S-217622 on VeroE6 / transmembrane serine protease 2 (TMPRSS2) cells evaluated the antiviral potential of clinical candidates.

Antiviral agent Effectiveness of Measured S-217622 In vivo In mice infected with the SARS-CoV-2 gamma strain.Interactions between receptor binding domains (RBDs) Spike protein The gamma strain and angiotensin converting enzyme 2 (ACE2) were promoted by mutations in RBD.

result

Research results show that compound 1 had In vitro Metabolic stability of 97% and 71%, respectively, as measured after 30 minutes incubation in human and rat microsomes. Clearance of 7.3 mL / min / mg and 111% oral bioavailability (F) were observed in in vivo PK studies performed in rats. Degradation of the X-ray complex structure of compound 1 with 3CLpro revealed that the binding mode of compound 1 is similar to that of proteases.

Compared to compound 1, S-217622 showed a 90-fold increase in enzyme inhibitory activity while maintaining its drug metabolism and pharmacokinetic (DMPK) profile. S-217622 also showed biochemical activity at IC⁵⁰ 0.013 μM value and EC antiviral activity⁵⁰ A value of 0.37 μM. In addition, there are oral dose-related DMPK profiles such as 96% and 88% high metabolic stability in human and rat microsomes, 97% high oral absorption, and a low clearance rate of 1.70 mL / min / mg in rats. It was observed.

S-217622 also showed significant DMPK levels in dogs and monkeys compared to rats and had a longer half-life

The antiviral activity of S-217622 against SARS-CoV and SARS-CoV-2 was similar, especially at sites where 3CLpro homology was well conserved. S-217622 also showed strong antiviral potential against Middle East Respiratory Syndrome (MERS), human coronavirus OC43 (HCoV-OC43), and human coronavirus 229E (HCoV-229E). S-217622 showed no inhibitory effect on the following host cell proteases. Cathepsin B / D / G / L, caspase-2, chymotrypsin, and thrombin up to 100 μM. It shows high specificity for coronavirus proteases.

Conclusion

Current findings show how the SBDD strategy is also The search for a non-peptidic 3CLpro inhibitor to find oral therapy for COVID-19 led to clinical candidate S-217622. Structural optimization based on the SBDD strategy has enabled 600 times better clinical activity with the good DMPK profile obtained with the S-217622. This drug candidate had a favorable preclinical profile as an oral treatment for the treatment of COVID-19.

Important antiviral activity of S-217622, In vivo Long t_1/2 For dogs and monkeys, excellent oral bioavailability, and In vivo A mouse model infected with SARS-CoV-2 prompted clinical trials for S-217622. This treatment candidate also exhibits significant antiviral activity against a wide range of coronavirus variants, demonstrating potential therapeutic agents in future coronavirus-induced pandemics.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.