Enzyme inhibitors acids, based

Interactions with metabolic enzymes fluorinated amino acids are peptidomi-metic units or reactive entities used to design either reversible enzyme inhibitors (analogues of substrates) or irreversible enzyme inhibitors (mechanism-based inhibitors). 

A significant difference between pseudoirreversible inhibitors and mechanism-based inactivators is the reversibiUty of the inactivation. A complete evaluation of the mechanism involved would require evidence not only for the covalent enzyme-inhibitor complex, but also for its decomposition products and its rate of reactivation. It is often difficult to identify the active site amino acid residue covalently linked to the inhibitor because of the instabiUty of the complex. 

Metalloenzymes, 33 40, see also Enzymes crystal structure, 44 230-258 DNA repair, 45 251 inhibitors, 36 40-42 molybdenum, 45 2, 53, 60-63 nuleic acid hydrolysis, 45 251-252 superoxide dismustases and, 45 130 zinc-containing, hard and soft acid-base behavior, 42 103-109 Metalloids... 

Enzyme-sensitive supramolecular polymers also hold promise in analytical applications such as the screening of enzyme inhibitors. A simple visual assay based on the hydrogelation of small molecules has been developed for screening the activities of inhibitors of enzymes like acid phosphatase. A number of inhibitors for... 

Some boronic acid-based enzyme inhibitors undergo strong yet reversible covalent attachment to a nucleophile at the enzyme s active site, while others simply act as competitive inhibitors in their borate conjugate base form. Boronic acid-based inhibition of thrombin has been achieved <93MI109>, and that of P-lactamases has been particularly effective <95TL8399, 96M1688>. When compared to other covalent transition-state analog inhibitors of P-lactamases like phos-... 

Irreversible inhibitors combine or destroy a functional group on the enzyme so that it is no longer active. They often act by covalently modifying the enzyme. Thus a new enzyme needs to be synthesized. Examples of irreversible inhibitors include acetylsal-icyclic acid, which irreversibly inhibits cyclooxygenase in prostaglandin synthesis. Organophosphates (e.g., malathion, 8.10) irreversibly inhibit acetylcholinesterase. Suicide inhibitors (mechanism-based inactivators) are a special class of irreversible inhibitors. They are relatively unreactive until they bind to the active site of the enzyme, and then they inactivate the enzyme. 

The discovery of Zanamivir as a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis and structure-activity relationship studies of Neu5Ac2en-based compounds as potential sialidase inhibitors. Exploration of these SAR studies were undertaken to optimize inhibitory activity and to improve the physicochemical properties of the sialic acid-based influenza virus sialidase inhibitor. A few in vitro assays are commonly employed to measure the effectiveness of influenza virus sialidase inhibitors. The first involves a fluorometric assay that measures release of a synthetic fluorophore following its cleavage from Neu5Ac by sialidase. Dye-uptake assay, such as the Neutral Red uptake assay, measures the uptake of a vital stain, Neutral Red in cell culture. The process requires intact membranes and active metabolism in the cell, and is expressed as percent protective rate against virus infection. The plaque-reduction assay is used to measure sialidase inhibition indirectly in cell culture, and provides some measure of the inhibitor s effect on the viability of the influenza virus. In vitro and in vivo systems for analysis of inhibitors of influenza virus enzymes have been reviewed.71... 

The drawback of this highly potent class of inhibitors is their toxicity (Stryer 1988). Only few representatives are known to be non-toxic. Therefore, enzyme inhibitors that are not based on amino acids are only of theoretical interest for oral drug delivery and other applications in human. Nevertheless, they might be interesting as lead compounds to develop novel potent and nontoxic inhibitors. 

---