User:Erdohert/sandbox

Proteasome inhibitors[edit]
Main article: Proteasome inhibitor

Chemical structure of bortezomib(Boronated form of MG132), a proteasome inhibitor used in chemotherapy that is particularly effective against multiple myeloma

Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (carbon = pink, nitrogen = blue, oxygen = red, boron= yellow), surrounded by the local protein surface. The blue patch is the catalytic threonine residue whose activity is blocked by the presence of bortezomib.

Proteasome inhibitors have effective anti-tumor activity in cell culture, inducing apoptosis by disrupting the regulated degradation of pro-growth cell cycle proteins.[74] This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials.

Lactacystin, a natural product synthesized by Streptomyces bacteria, was the first non-peptidic proteasome inhibitor discovered[87] and is widely used as a research tool in biochemistry and cell biology. Lactacystin was licensed to Myogenics/Proscript, which was acquired by Millennium Pharmaceuticals, now part of Takeda Pharmaceuticals. Lactacystin covalently modifies the amino-terminal threonine of catalytic β subunits of the proteasome, particularly the β5 subunit responsible for the proteasome's chymotrypsin-like activity. This discovery helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease.

Bortezomib (Boronated MG132), a molecule developed by Millennium Pharmaceuticals and marketed as Velcade, is the first proteasome inhibitor to reach clinical use as a chemotherapy agent.[88] Bortezomib is used in the treatment of multiple myeloma.[89]Notably, multiple myeloma has been observed to result in increased proteasome-derived peptide levels in blood serum that decrease to normal levels in response to successful chemotherapy.[90] Studies in animals have indicated that bortezomib may also have clinically significant effects in pancreatic cancer.[91][92] Preclinical and early clinical studies have been started to examine bortezomib's effectiveness in treating other B-cell-related cancers,[93] particularly some types of non-Hodgkin's lymphoma.[94] Clinical results also seem to justify use of proteasome inhibitor combined with chemotherapy, for B-cell acute lymphoblastic leukemia [95] Proteasome inhibitor can kill some types of cultured leukemia cells that are resistant to glucocorticoid.[96]

The molecule ritonavir, marketed as Norvir, was developed as a protease inhibitor and used to target HIV infection. However, it has been shown to inhibit proteasomes as well as free proteases; to be specific, the chymotrypsin-like activity of the proteasome is inhibited by ritonavir, while the trypsin-like activity is somewhat enhanced.[97]Studies in animal models suggest that ritonavir may have inhibitory effects on the growth of glioma cells.[98]

Proteasome inhibitors have also shown promise in treating autoimmune diseases in animal models. For example, studies in mice bearing human skin grafts found a reduction in the size of lesions from psoriasis after treatment with a proteasome inhibitor.[99] Inhibitors also show positive effects in rodent models of asthma.[100]

"Recently, proteasome inhibitors have also been cited as a promising target for anti-Malarial drugs. The Plasmodium falciparum parasite, which causes malaria, can be targeted by proteasome inhibitors throughout its life cycle. The difficulty has been in identifying a proteasome inhibitor which is not toxic to the human hosts. By preferentially targeting the β2-subunit, scientists have now been able to target the Plasmodium proteasome, which may serve as a useful tool for the next anti-marlarial drugs. "

Labeling and inhibition of the proteasome is also of interest in laboratory settings for both in vitro and in vivo study of proteasomal activity in cells. The most commonly used laboratory inhibitors are lactacystin and the peptide aldehyde MG132 initially developed by Goldberg lab. Fluorescent inhibitors have also been developed to specifically label the active sites of the assembled proteasome.[101]

What I plan to edit:

I found a new article in Nature detailing how proteasome inhibitors can be used to target increased drug resistance in the malaria parasite.

"Recently, proteasome inhibitors have also been cited as a promising target for anti-Malarial drugs. The Plasmodium falciparum parasite, which causes malaria, can be targeted by proteasome inhibitors throughout its life cycle. The difficulty has been in identifying a proteasome inhibitor which is not toxic to the human hosts. By preferentially targeting the β2-subunit, scientists have now been able to target the Plasmodium proteasome, which may serve as a useful tool for the next anti-marlarial drugs. "

citation is listed after the part I added with the [1]