Development of small molecule inhibitors of the SARS-CoV-2 protease PLpro for the treatment and prevention of Covid-19

The VirDUB program funded by the Australian government, initiated screening and hit identification against the viral protease PLpro. The program has been remarkably successful, revealing new inhibitor scaffolds.

Funding from the Wellcome Trust will enable us to advance our two best series through the Hit-to-Lead stage, to arrive at Lead compounds on path for clinical development.

We request funding for a structurally guided medicinal chemistry campaign, led by WEHI scientists, to (i) increase compound activity against PLpro, (ii) establish antiviral efficacy against SARS-CoV-2 in vitro and in vivo and (iii) improve pharmacological properties of lead compounds.

We envisage to deliver 1-2 chemical series with promising pharmacological properties for oral administration, together with a complete structural understanding to assess future efficacy against PLpro variants from SARS-CoV-2 and future Coronaviruses.

Established series will be protected and partnered with industry to develop Lead molecules into clinical drugs, exploiting the excellent track record and existing network of WEHI BDO.

Moreover, a second program at WEHI targeting the Mpro protease of SARS-CoV-2, enables unprecedented ability to pool resources, critically assess results, and engage in synergy studies. This combination of assets at a globally leading Institute will be highly attractive for industry partners.