Orally Available covalent irreversible 3CLPro Inhibitor for the Treatment of COVID-19 and Coronavirus infection (Phase I)
Owned and Available for Licensing
In vivo efficacy studies – SARS-CoV-2 Omicron BA2.3 variant
In vivo efficacy studies – SARS-CoV-2 WT variant
In vivo efficacy studies – MERS-CoV
In vivo PK studies
In vitro ADMET studies
In vitro cell-based
The 3CLPro (3CL protease) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses. it cleaves peptide bonds to release nsp4 to nsp16 including itself. The 3CLPro of SARS-CoV-2 exhibits a high degree of sequence conservation across different variants. Hence this makes it an attractive drug target for SARS-CoV-2 and other coronaviruses.
Pictures referred from Funakoshi and Viralzone
Insilico Medicine 3CLPro Inhibitor Summary – Phase I
Strong inhibition against all human coronavirus 3CLPro Broad antivirus activity against multiple strains & variants
Possibility to overcome Nirmatrelvir clinical resistance
Novel binding mode Lower efficacious dose
Kinact/Ki suggests high efficiency of covalent bond formation
Enzymatic dilution assay confirms the unique irreversible binding nature
Enables different PK/PD correlation vs Nirmatrelvir
Promising druggability Oral single agent
Superior passive permeability in Caco-2 assay compared to Nirmatrelvir
Lower efficacious dose in mouse models
No CYP/transporter inhibition concern
Low risk of CYP induction
High synthetic feasibility
2-step synthesis from simple commercially available starting materials
Stable salt & crystal form
Practical API production without SFC or HPLC purification
By February 2023, more than 700 Million confirmed cases of COVID-19, including 6 Million deaths globally were reported by World Health Organization (WHO). The real number of deaths was likely underestimated given the wide spread of Omicron (BA.5, BA. 2.75 and XBB 1.5). WHO still regards the ongoing COVID-19 pandemic as a public health emergency of international concern (PHEIC) on February 1st, 2023.
3CLPro is highly conserved in the genus coronavirus including MERS-CoV, SARS-CoV and other respiratory coronaviruses and its inhibition blocks the release of nsp4 to nsp16, especially nsp12 (also RdRp) that are essential for coronavirus replication. This 3CLPro becomes an attractive target for treatment of COVID-19 because it exhibits a lower rate of mutation compared to 5 proteins in all discovered variants. Moreover, given the 3CLPro enzyme's role in viral replication, its potential for mechanistic safety, and expected lack of spike protein resistance variant challenges, its inhibition by a small molecule inhibitor seems attractive.
Project Status – Phase I
Insilico Medicine initiated an AI-designed program targeting 3CL protease and nominated a preclinical candidate for COVID-19 targeting 3CLPro. The ISM compound has favorable in vitro ADME properties and antivirus profile against different coronaviruses and their variants. Preliminary safety data indicates that the ISM compound is well tolerated as a single agent. The data supports the clinical evaluation of the ISM compound as a 3CL inhibitor in COVID-19 and the strategic reserve for future coronavirus pandemics.