WEHI Wednesday Seminar hosted by Professor Guillaume Lessene

Dr Rohan Volpe

Senior Research Officer – National Drug Discovery Centre (Operations & Medicinal Chemistry), New Medicines and Diagnostics division

Dr Marija Dramicanin

Head – Protein Production Facility, Advanced Technology & Biology division

Development of an Oral Antiviral from a High-throughput Screen Against the SARS-CoV-2 Main Protease (Mpro)

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

In response to the COVID-19 pandemic, WEHI began a drug discovery campaign in early 2020 to identify novel small molecule inhibitors of Mpro, a viral protease essential for SARS-CoV-2 replication. The SARS-CoV-2 virus causes COVID-19 and is related to other highly pathogenic coronaviruses (SARS-CoV-1, MERS-CoV). Mpro inhibition is now clinically validated as a COVID-19 treatment, being the antiviral mechanism of Paxlovid (nirmatrelvir/ritonavir, Pfizer, provisionally approved by the TGA, Jan. 2022) and ensitrelvir (Shionogi, approved in Japan, Mar. 2024).

Here we will describe the identification of multiple compounds as hits from a high-throughput screen against SARS-CoV-2 Mpro, followed by selection and development of a lead hit series into an orally active Mpro inhibitor. This work was completed by a large team from WEHI in collaboration with the CDCO at Monash.

Screening ~400 000 compounds at the NDDC against Mpro and subsequent hit validation in orthogonal assays resulted in the identification of several promising hits for further development as inhibitors. X-ray co-crystal structure-guided design focussed on the leading hit and resulted in a series of potent Mpro inhibitors. Further modifications of this series improved drug-like properties (e.g. metabolic stability, solubility) and potency, with two compounds progressing to in vivo pharmacokinetic studies. The lead compound selected from these studies demonstrated in vivo efficacy in a mouse SARS-CoV-2 infection model to a level equivalent to the clinically used Mpro inhibitor ensitrelvir.

All welcome!