Cysteine proteases are protein processing and protein degrading enzymes whose overexpression in human body results in serious pathological changes, such as neurodegenerative diseases (e.g.Alzheimer's, multiple sclerosis, ischemic stroke, myocardial infarcts, cataract formation, etc.), destruction of cartilage tissue, and bone atrophy. Other cysteine proteases play an essential role in life cycles of some viruses (e.g. coronavirus) and parasites (e.g. malaria). The affinity labeling agents used as inhibitors of cysteine proteases normally bear an electrophilic �warhead�, a reactive group that covalently binds the active site cysteine residue thereby inactivating the enzyme. Examples include Michael acceptors, 1,2-diketones, and three-membered ring heterocycles (e.g. aziridines, epoxides), the latter generally having greater potency, but lower selectivity, often affecting aspartate and serine proteases as well. Among carbocyclic unsaturated three-membered ring compounds, only BDA-410, a cyclopropenone derivative, has been used as a cysteine protease inhibitor, but its binding appears to be reversible, which suggests the addition of the thiol group to the 3-carbonyl, rather than to the cyclopropene double bond. Several derivatives of cyclopropenes have been synthesized and evaluated as potential cysteine-binding �warheads�. Their stability and reactivity toward cysteine and other amino acid chemical probes was examined. The 1,2-cyclopropene moiety irreversibly binds the thiol group of cysteine, leaving other amino acid residues unaffected, which has the advantage for targeting enzymes expressed in foreign organisms or promoting carcinoma progression (e.g. cathepsins L, B, H, and S).

Cyclopropenes as warheads for inhibitors of cysteine proteases

247th National Meeting (2014)

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