Many existing drugs are designed to bind to the active sites and then suppress
protein activities that promote the development of disease progress.
For example, cocktails of protease inhibitors are used to therapeutically
block hepatitis C virus infections (Fattori et al., 2000) by inactivating the
viral NS3 protease (Barbato et al., 2000). Statins are low molecular-weight
compounds that suppress HMG-CoA reductase activity and, thus, cholesterol
synthesis, to therapeutically assist patients at risk for coronary heart
disease (Penzak, Chuck, & Stajich, 2000). RNA aptmers are also used as
protease inhibitors .
There are some drawbacks to the use of viral-associated protein targets for drug selection. In the case of HIV-associated diseases, rapid genetic drift in protein sequences makes viral targets immunoevasive. Therefore, these protein sequences are less attractive targets for long-term therapeutic strategies.
Most AD patients are currently treated with acetylcholinesterase inhibitors, which act as cognitive enhancers. Acetylcholinesterase inhibitors (e.g., Aricept, Eisai Co Ltd, Tokyo, Japan; Pfizer Inc., New York, NY) are proteintargeted inhibitors of the esterase that cleaves acetylcholine, the cholinergic neurotransmitter. These drugs slow down the rate of cognitive decline by increasing acetylcholine neurotransmitter levels in the brain (al-Jafari, Kamal, Greig, Alhomida, & Perry, 1998). The anticholinesterases provide limited improvement of cognitive performance in AD patients, and thus are of only partial benefit to AD patients early in disease progression. One problem associated with the use of anticholinesterases is that they have not been shown to confer any therapeutic action on the neuropathological events that might cause AD (i.e., amyloid, apolipoprotein E, alpha-1 antichymotrypsin, heparan sulfate proteoglycans, and the microtubule-associated protein, tau). We will discuss our discovery that a new anticholinesterase, phenserine, directly suppresses APP mRNA translation through the 5'UTR, thus imparting a therapeutic impact on A(3-peptide buildup, in addition to being an anticholinesterase (Shaw, Utsuki, Rogers, Yu, Lahiri, & Grieg, 2001). Current protein-based therapeutic approaches for AD aim to arrest the accumulation of the major amyloid plaque-associated protein, the A(3 peptide. The exact mechanism by which amyloid becomes toxic is unknown, but the presence of copper and iron and oxidative stress is a critical event (Huang et al., 1999; Bush et al., 2000). At the same time, neurotoxic protofibrils deposit in the neuritic amyloid plaques as Ap peptide is converted from an open-coil structure into a beta-sheet conformation (Kimberly, Xia, Rahmati, Wolfe, & Selkoe, 2000; Teplow, 1998; Walsh et al., 1999). Haass et al. (1992) first showed that Ap peptide is secreted from all cells in the body after being cleaved from the transmembrane APP. The elegant work of Wolfe et al. (1999) demonstrated that two transmembrane aspartates in presenilin-1 constitute the endoproteolytic peptidase conferring y-secretase activity. Thus, PS-1 mutations cause familial AD (Levy- Lahad, 1995; Scheuner et al., 1996), and PS-1 appears to function as the y-secretase that catalyzes the final cleavage of APP to Ap (Wolfe et al., 1999).
Companies, including Bristol-Myers Squibb, have programs to screen, from large combinatorial libraries, for small molecules that can suppress the secretases (PS-1 and PS-2) that cleave APP to the 40-42 amino acid Ap peptide. One drawback of developing drugs that inhibit both (3 and y-secretase activity (and hence the generation of A(3 peptide) is that these secretases have other cellular targets. For example, the transcription factor notch is cleaved by PS-1, and it remains to be seen whether drug-induced inhibition of y-secretase will generate cytotoxic side effects associated with the disappearance of an essential downstream transcriptionally activated protein (Song et al., 1999). This concern was addressed by recent work showing that transfectants bearing PS-1 and PS-2 mutations maintain nuclear translocation of notch to the nucleus with relative preservation of notch-1 signaling (Berezovska et al., 2000). However, new protease inhibitors directed toward (3- and y-secretases may also affect other unrelated cellular targets, although this subject remains open to the development of a drug that proves the concept
There are some drawbacks to the use of viral-associated protein targets for drug selection. In the case of HIV-associated diseases, rapid genetic drift in protein sequences makes viral targets immunoevasive. Therefore, these protein sequences are less attractive targets for long-term therapeutic strategies.
Most AD patients are currently treated with acetylcholinesterase inhibitors, which act as cognitive enhancers. Acetylcholinesterase inhibitors (e.g., Aricept, Eisai Co Ltd, Tokyo, Japan; Pfizer Inc., New York, NY) are proteintargeted inhibitors of the esterase that cleaves acetylcholine, the cholinergic neurotransmitter. These drugs slow down the rate of cognitive decline by increasing acetylcholine neurotransmitter levels in the brain (al-Jafari, Kamal, Greig, Alhomida, & Perry, 1998). The anticholinesterases provide limited improvement of cognitive performance in AD patients, and thus are of only partial benefit to AD patients early in disease progression. One problem associated with the use of anticholinesterases is that they have not been shown to confer any therapeutic action on the neuropathological events that might cause AD (i.e., amyloid, apolipoprotein E, alpha-1 antichymotrypsin, heparan sulfate proteoglycans, and the microtubule-associated protein, tau). We will discuss our discovery that a new anticholinesterase, phenserine, directly suppresses APP mRNA translation through the 5'UTR, thus imparting a therapeutic impact on A(3-peptide buildup, in addition to being an anticholinesterase (Shaw, Utsuki, Rogers, Yu, Lahiri, & Grieg, 2001). Current protein-based therapeutic approaches for AD aim to arrest the accumulation of the major amyloid plaque-associated protein, the A(3 peptide. The exact mechanism by which amyloid becomes toxic is unknown, but the presence of copper and iron and oxidative stress is a critical event (Huang et al., 1999; Bush et al., 2000). At the same time, neurotoxic protofibrils deposit in the neuritic amyloid plaques as Ap peptide is converted from an open-coil structure into a beta-sheet conformation (Kimberly, Xia, Rahmati, Wolfe, & Selkoe, 2000; Teplow, 1998; Walsh et al., 1999). Haass et al. (1992) first showed that Ap peptide is secreted from all cells in the body after being cleaved from the transmembrane APP. The elegant work of Wolfe et al. (1999) demonstrated that two transmembrane aspartates in presenilin-1 constitute the endoproteolytic peptidase conferring y-secretase activity. Thus, PS-1 mutations cause familial AD (Levy- Lahad, 1995; Scheuner et al., 1996), and PS-1 appears to function as the y-secretase that catalyzes the final cleavage of APP to Ap (Wolfe et al., 1999).
Companies, including Bristol-Myers Squibb, have programs to screen, from large combinatorial libraries, for small molecules that can suppress the secretases (PS-1 and PS-2) that cleave APP to the 40-42 amino acid Ap peptide. One drawback of developing drugs that inhibit both (3 and y-secretase activity (and hence the generation of A(3 peptide) is that these secretases have other cellular targets. For example, the transcription factor notch is cleaved by PS-1, and it remains to be seen whether drug-induced inhibition of y-secretase will generate cytotoxic side effects associated with the disappearance of an essential downstream transcriptionally activated protein (Song et al., 1999). This concern was addressed by recent work showing that transfectants bearing PS-1 and PS-2 mutations maintain nuclear translocation of notch to the nucleus with relative preservation of notch-1 signaling (Berezovska et al., 2000). However, new protease inhibitors directed toward (3- and y-secretases may also affect other unrelated cellular targets, although this subject remains open to the development of a drug that proves the concept
No comments:
Post a Comment