(602d) Molecular Modeling Aided Inhibitor Design to Target Human Cathepsin L Has Shown Promise In Finding Therapeutics to Block Sars and Ebola Infection

Wang, T., University of Pennsylvania
Shah, P. P., University of Pennsylvania
Kaletsky, R. L., University of Pennsylvania
Greenbaum, D. C., University of Pennsylvania
Bates, P., University of Pennsylvania
Diamond, S. L., University of Pennsylvania

A thiocarbazate compound was initially identified as a potent cathepsin L (EC inhibitor via an HTS effort at Penn Centre for Molecular Discovery. Molecular docking technique was employed to explore the interaction between the inhibitor and the enzyme and identified particular moieties responsible for binding affinity.

These efforts have led to the discovery of a tetrahydroquinoline oxocarbazate (PubChem CID 23631927) which was tested to be an nM inhibitor of human cathepsin L and an entry blocker of SARS coronavirus and Ebola pseudotype virus. The compound demonstrated activity in blocking both SARS-CoV (IC50 = 273±49 nM) and Ebola virus (IC50 = 193±39 nM) entry into HEK 293T cells while the thiocarbazate compound did not show efficacy in the assay. In an attempt to trace the intracellular action of the inhibitors with intracellular cathepsin L, the activity based probe DCG-04 was used to label the active site of cysteine proteases in 293T lysates. The reduction in active cathepsin L in inhibitor treated cells correlated well with the observed potency of inhibitors observed in the virus pseudotype infection assay. This experiment helped explain the observed difference in potency and further confirmed the validity of targeting cathepsin-L to find therapeutics for SARS and Ebola infection.


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