Toxoplasma gondii (T. gondii) infection in the brain is associated with neurological disorder and encephalitis. Currently, there exists no T. gondii therapeutic capable of crossing the blood-brain barrier (BBB). Recently, Cathepsin L (CatL), a cysteine protease, was shown to be necessary for the proliferation of T. gondii in the host. Several known inhibitors of Homo sapiens CatL (HsCatL), known to target CatL over other cathepsins, were selected and characterized by computation. Computational modeling was utilized to identify those featuring physio-chemical properties most likely to diffuse through the BBB. Careful examination of the crystal structures of HsCatL and T. gondii CatL (TgCatL) revealed certain differences in peptide sequence that may allow for selectivity between species. A reliable synthetic pathway was established for the lead and the derived analogues. Fifteen analogues were produced to begin establishing a structure-activity relationship and pharmacophore model.

Design and synthesis of potential CNS-permeable inhibitors of T. gondii Cathepsin L

251st National Meeting (2016)

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