The single‐atom enzyme (SAE) is a novel type of nanozyme that exhibits extraordinary catalytic activity. Here, we constructed a PEGylated manganese‐based SAE (Mn/PSAE) by coordination of single‐atom manganese to nitrogen atoms in hollow zeolitic imidazolate frameworks. Mn/PSAE catalyzes the conversion of cellular H2O2 to .OH through a Fenton‐like reaction; it also promotes the decomposition of H2O2 to O2 and continuously catalyzes the conversion of O2 to cytotoxic .O2− via oxidase‐like activity. The catalytic activity of Mn/PSAE is more pronounced in the weak acidic tumor environment; therefore, these cascade reactions enable the sufficient generation of reactive oxygen species (ROS) and effectively kill tumor cells. The prominent photothermal conversion property of the amorphous carbon can be utilized for photothermal therapy. Hence, Mn/PSAE exhibits significant therapeutic efficacy through tumor microenvironment stimulated generation of multiple ROS and photothermal activity.

Cysteine proteases are an important class of enzymes involved in the degradative processing of peptides and proteins. 1,2 They are ubiquitous in nature and play vital roles in numerous physiological processes including arthritis, osteoporosis, Alzheimer's disease, cancer cell invasion, and apoptosis. 1-3 Cysteine proteases are also essential to the life cycles of many pathogenic protozoa. 4,5 One such parasite is Trypanosoma cruzi, the etiologic agent of Chagas' disease. Cruzain, 6,7 the major cysteine protease of T. cruzi, has been identified as a potential therapeutic target for treatment of Chagas' disease. [7][8][9] Several strategies have been pursued in the design of cysteine protease inhibitors. 2,10,11 Peptidyl aldehydes, 12 diamino ketones, 13 and nitriles 14 are reversible inhibitors that form hemithioacetals, peptide ketals, and thioimidates, respectively, with the thiol of the active site cysteine residue, mimicking the initial covalent enzyme adduct in normal proteolytic turnover. Epoxysuccinyl derivatives, 15 peptidyl Michael acceptors, 16-18 (acyloxy)methyl ketones, 19 and halomethyl ketones are examples of inhibitors which irreversibly inactivate cysteine proteases via alkylation of the active site cysteine residue. Several classes of nonpeptidic reversible inhibitors of cysteine proteases also have been described. [20][21][22] In connection with efforts to develop potent and selective inhibitors of cruzain, we became interested in the vinyl sulfone inhibitor series first introduced by Hanzlik 17 and further developed by Palmer et al. 18,23 Compound 1a is a potent and selective inhibitor of cruzain, with a second-order rate constant (k inact /K i ) of 203 000 s -1 M -1 . 18 Inhibitors 1a and especially 1b have also proven highly effective against T. cruzi, both in tissue culture and in vivo experiments (mouse model). 24 Although considerable effort has been devoted to the optimization of interactions of inhibitors with the cruzain S 1 and S 2 binding sites, 18,23,25 virtually nothing is known about the interactions of substrates or inhibitors with the S 1 ′ and S 2 ′ sites. The prime site region in cruzain contains a large open surface defined by Trp 177, and available X-ray structures suggest that there is considerable room for prime site inhibitor binding. 7,13,22,25 A recent X-ray structure of cathepsin K, the active site of which is homologous to that of cruzain, with covalently bound APC3328, a dipeptidyl phenyl vinyl sulfone inhibitor related to 1b, reveals that the phenyl residue of the phenyl sulfonyl unit does not make optimal interactions with prime site residues. 26 Accordingly, we decided to probe the possibility that additional selectivity and potency in the vinyl sulfonyl series could be achieved by extending the inhibitor structure into the prime site region, via modification of the sulfonyl substituent as suggested by structure 2. However, we anticipated that it might be easier to synthesize a family of vinyl sulfonamides 3 or vinyl sulfonate esters 4, using the vinyl sulfonyl chl...

The series of vinyl-sulfone-based inhibitors examined in complex with cruzain was designed to probe recognition and binding potential of an aromatic-rich region of the enzyme. Analysis of the interactions formed shows that aromatic interactions play a less significant role, whereas the strength and importance of hydrogen bonding in the conformation adopted by the inhibitor upon binding to the enzyme was highlighted. A derivative of one inhibitor examined is currently under development as a therapeutic agent against Chagas' disease.