Potent inhibitors

A major concern when remediating wood-treatment sites is that pentachlorophenol was often used in combination with metal salts, and these compounds, such as chromated copper—arsenate, are potent inhibitors of at least some pentachlorophenol degrading organisms (49). Sites with significant levels of such inorganics may not be suitable candidates for bioremediation. 

In contrast to the situation with the alternative nitrogenases, but with the notable exception of the C. pasteurianum proteins, the component proteins from aU. Mo-based nitrogenases interact as heterologous crosses to form catalyticaHy active enzymes (52). Carbon monoxide, CO, is a potent inhibitor of aU. nitrogenase-cataly2ed substrate reductions, with the exception of reduction (126). Molecular hydrogen has a unique involvement with Mo-nitrogenase... 

The phosphorodithioates DNA derivatives have been shown to bind specifically to complementary DNA or ENA sequences to form stable adducts. Because they are also highly resistant to degradation by cellular exonucleases, these derivatives can be useful both for appHcations in research and as therapeutic dmgs. Phosphorodithioate DNA has been shown to stimulate Rnase H activity in nuclear cell extracts and is a potent inhibitor of HIV type-1 reverse transcriptase (56). 

Several methods are being studied to enhance the stabiUty of peptide mimics and improve their stereochemical similarity to the endogenous peptides. For example, the tetrapeptide Cys—Val—Phe—Met, a potent inhibitor of Ras famesyltransferase, is proposed to exist in a turned conformation, which mimics the endogenous peptide during enzyme binding. This conformation is successhiUy mimicked by 3-amino-l-carboxymethyl-5-phenyl-benzodiazepin-2-onederivatives (198) (142). 

Rifampicin has also shown antiviral activity but at levels 500—1000 times greater than required for antibacterial activity (130,140—142). Rifampicin shows promise in the treatment of leprosy (130,143). A large number of rifampicinlike derivatives are potent inhibitors of reverse transcriptase (123,144-148). 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Thraustomycin. Thraustomycin and P-thraustomycin are isolated from S. exfoliatus (4). Although their stmctures have not been totally elucidated, hydrolysis of thraustomycin shows that it contains equimolar quantities of adenine, L-leucine, and a tetrahydroxymonocarboxyhc acid. Thraustomycin is a potent inhibitor of the fungus, Af. hiemallis (+), but does not inhibit bacteria. 

Griseolic Acids. The three griseoHc acids. A, B, and C (46—48), have been isolated from S. griseoaurantiacus (1,142). They are potent inhibitors of... 

Oxanosine. Oxanosiae (50), which is isolated from S. capreolus (1,148), is a potent inhibitor of GMP synthetase and nucleic acid synthesis (149,150). 

The nucleotide form of ribavirin does not manifest its antiviral activity simply by lowering the GTP levels, but may indeed participate directly in binding to specific G proteins (124). Ribavirin has recently been studied as an inhibitor of vesicular stomatitis vims and La Crosse vims (125). Of the phosphorylated forms of the dmg, ribavirin-5 -diphosphate was by far the most potent inhibitor of viral repHcation for these two vimses. 

Himdin [8001-27-2] is a polypeptide of 66 amino acids found ia the saUvary gland secretions of the leech Himdo medicinalis (45). It is a potent inhibitor of thrombin and biads to y-thrombia with a dissociation constant of 0.8 x 10 ° M to 2.0 x lO " M. Himdin forms a stable noncovalent complex with free and bound thrombin completely iadependent of AT-III. This material has now been cloned and expressed ia yeast cells (46,47). Its antigenic poteatial ia humans remains to be estabUshed. 

Argatroban [74863-84-6] ((2R,4R)-4-methyl-l-[A/ -)(3 methyl l,2,3,4-tetrahydto-8-quiaoIiaesulfonyl)-L-atgiayl]-2-piperidiaecatboxyhc acid monohydrate) is a potent inhibitor of thrombin formation and activity (49). This agent has been studied in vitro and ia a few animal models. Its toxicity and activity ia humans ate unknown. 

Verapamil. Verapamil hydrochloride is a pbenyl alkyl amine and is considered the prototype of the Class I calcium channel blockers. Verapamil is also a potent inhibitor of coronary artery spasm and is useful in Prinzmetal s angina and in unstable angina at rest. Verapamil produces negative chronotropic and inotropic effects. These two actions reduce myocardial oxygen consumption and probably account for the effectiveness of verapamil in chronic stable effort angina (98,99). Moreover, verapamil is an effective antihypertensive agent. 

When plating any substrate less noble than copper, only a few mg/L of dissolved copper in the acid baths can adversely affect adhesion. Coatings can be too thin to be visible, yet contribute to poor adhesion. Small additions of thiourea have been used to prevent copper immersion, but it acts as a potent inhibitor, and work should be re-electrocleaned after the acid. Work should be exposed to the mildest acid treatments possible. Over-etching should be avoided. 

At the molecular level, microcystins are potent inhibitors of protein phosphatases 1 and 2A. The activity of protein phosphatases can be determined by measuring... 

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