Oral Presentation Royal Australian Chemical Institute National Congress 2026

Utilizing fragment-based drug design to develop a novel class of inhibitors for SARS-CoV-2 papain like protease. (136934)

Ashley Taylor 1 2 , Qiangqiang Wei 2 , Mahesh Barmade 2 , Kevin Teuscher 2 , Nagaraju Miriyala 2 , Tyson Rietz 2 , Kangsa Amporndanai 2 , Jordan Anderson-Daniels 2 , Chideraa Apakama 2 , John Sensintaffar 2 , Jason Phan 2 , Sarah Cherry 3 , Timothy Sheahan 4 , Mark Dennison 2 , Taekyu Lee 2 , Stephen Fesik 2
  1. Medicinal chemistry , Monash University Institute of Pharmacy and Pharmaceutical Science., Melbourne, Vic, Australia
  2. Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
  3. Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, United States
  4. Epidemiology, University of North Carolina, Chappel Hill, North Carolina, United States

Over the last 2 decades there have been several viral outbreaks caused by members of the coronavirus family the largest being the COVID-19 pandemic of 2019-2022 which claimed over 7 million lives worldwide. Currently only 3 drugs have been approved by the FDA for the treatment of COVID-19, a main protease inhibitor (Nirmatrelvir) and 2 RNA dependant RNA polymerase inhibitors (Remdesivir and Molnupiravir). Although these drugs have proven effective in the treatment of SARS-CoV-2, the emergence of drug-resistant strains has limited their efficacy.1 This paired with the high probability of future coronaviral outbreaks highlights the need to develop therapeutics with novel mechanisms of action

The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. To date almost all reported PLPro inhibitors have been derived from GRL-0617 - a PLPro inhibitor developed against SARS-CoV-1 in 2008 - with no candidates progressing to clinical trials.2 We have conducted a fragment-based screen of SARS-CoV-2 PLPro identifying a novel class of spiro chromanone inhibitors that bind adjacent to the active site. Subsequent fragment growing and merging strategies guided heavily by 30+ high resolution X-ray cocrystal structures have led to a greater than 10,000-fold increase in binding affinity with lead compounds displaying low nanomolar activity in biochemical and cellular antiviral assays. This presents an opportunity to develop a new class of anti-coronaviral medication suitable for current and future pandemics.

  1. Iketani, S., et al. (2023). "Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir." Nature 613(7944): 558-564.
  2. Ratia, K., et al. (2008). "A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication." Proceedings of the National Academy of Sciences 105(42): 16119-16124.