Protease inhibitor classes

The key in vitro resistance mutation to amprenavir appears to be I50V. Evidence to date suggests that cross-resistance to other members of the protease inhibitor class of drugs may be less prevalent with amprenavir than with previously available compounds. 

Pfizer, antidepressant] [Abbott, antiretroviral of the HIV-protease inhibitor class] [Hoffmann-La Roche, malaria]... 

So far, five different protease inhibitors have been approved by the FDA for the treatment of HIV infection [3, 4]. Clinical trials in which protease inhibitors were evaluated in monotherapy demonstrated the potency of this class of inhibitors (decrease in HIV RNA levels, increase in CD4 cell counts). Treatment regimens were subsequently broadened to include reverse transcriptase inhibitors in combination with protease inhibitors. The result of these clinical trials has led to a list of guidelines with recommendations for the optimal treatment options. Prolonged control of the infection with combination therapy (highly active antiretroviral therapy, HAART ) could be shown. 

Amprenavir (APV, Agenerase) is the most recently approved HIV protease inhibitor. It is smaller and stereochemically less complex than the other drugs in this class. Adsorption of this compound was found to be impaired by high fat meals. Common side effects of Amprenavir are nausea, vomiting, diarrhea, rash and a tingling sensation around the mouth. 

As with reverse transcriptase inhibitors, resistance to protease inhibitors may also occur. Mutations in the HIV protease gene were shown to confer resistance to each of the aforementioned molecules. In addition, passaging of viius in the presence of HIV protease inhibitors also gave rise to strains less susceptible to the original inhibitor or cross-reactive to other compounds in the same class. New Diug Targets... 

Currently, there is no approved antiviral therapy specifically targeting hepatitis C virus (HCV). The development of an HCV replicon system and our improved understanding of the structure and function of HCV proteins have led to the development of several classes of specific HCV inhibitors. NS3-4A protease inhibitors and NS5B polymerase inhibitors are furthest in development as discussed in Chaps. 2-4 (De and Migliaccio 2005 Manns et al. 2007 Pawlotsky et al. 2007). 

The most convenient way of categorizing the classes of cathepsin inhibitors is based on the nature of the electrophilic warhead that interacts with the sulfhydryl group of the active site cysteine residue. Since a large portion of the binding energy of a cysteine protease inhibitor comes from the covalent interaction with this thiol, the properties of the resulting molecules are largely derived from the electrophile. In broad terms, these inhibitors can be broken down into ketone and nitrile-based reversible covalent inhibitors, or the more recent non-covalent inhibitors based on an aminoaniline template. 

HIV protease inhibitors atazanavir, HepG2 Divergence in class, dislipidemia [25]... 

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

Milne et al. described the discovery of HIV-1 protease inhibitors based on a pharmacophore derived from X-ray crystal structures. After searching the NCI database with 206 000 entries and postfiltering the resulting hits, a total of 50 molecules were tested, leading to submicromolar activity for the best two compounds [286]. In their search for HIV-1 integrase inhibitors, another pharmacophore produced up to 340 hits, resulting in 10 structurally different classes and four compounds with affinities below 30 XM [287]. 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

Neff, N.T., DeMartino, G.N., and Goldberg, A.L. (1979). The effect of protease inhibitors and decreased temperature on the degradation of different classes of proteins in cultured hepatocytes. J. Cell Physiol. 101,439—457. 

Heparin has been found to bind a large number of proteins (Table 3). The biological activity of heparin and related polysaccharides is usually ascribed to their interaction with heparin-binding proteins. These proteins can be classified into classes including (1) enzymes, (2) protease inhibitors, (3) lipoproteins, (4) growth factors, (5) chemokines, (6) selectins, (7) extracellular matrix proteins, (8) receptor proteins, (9) viral coat proteins, (10) nuclear proteins, and (11) other proteins (1). Many heparin-binding proteins are enzymes and enzyme inhibitors. For example, proteases in the coagulation cascade, such as factors Ha, IXa, Xa, Xlla, and Villa, are heparin-... 

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

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