The therapeutic potential of advances in cysteine protease inhibitor design.
Cysteine proteases are attracting increased attention for therapeutic intervention by inhibitors because of an increased recognition of specific processing functions in both mammals and microbes. New advances in inhibitor design have been made for both reversible and irreversible classes. Reversible inhibitors may incorporate a covalent bond formation that can contribute an element of selectivity relative to serine protease inhibition. Ketones of low intrinsic reactivity are especially attractive agents, with potential for chronic therapeutic use. Effectively irreversible inhibition can be achieved with slow or single turnover substrates. This approach eliminates any reactivity toward non-enzyme nucleophiles. Only mechanistically related enzyme targets will be irreversibly blocked in an in vivo setting, thereby resulting in a safer type of inhibitor.
Veber
D F
DF
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. Daniel_F_Veber@sbphrd.com
Thompson
S K
SK