Academic literature on the topic 'Proteasome-like inhibitors'
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Journal articles on the topic "Proteasome-like inhibitors"
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Mitchell, Angela M., and R. Jude Samulski. "Mechanistic Insights into the Enhancement of Adeno-Associated Virus Transduction by Proteasome Inhibitors." Journal of Virology 87, no. 23 (September 11, 2013): 13035–41. http://dx.doi.org/10.1128/jvi.01826-13.
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Proteasome inhibitors (e.g., bortezomib, MG132) are known to enhance adeno-associated virus (AAV) transduction; however, whether this results from pleotropic proteasome inhibition or off-target serine and/or cysteine protease inhibition remains unresolved. Here, we examined recombinant AAV (rAAV) effects of a new proteasome inhibitor, carfilzomib, which specifically inhibits chymotrypsin-like proteasome activity and no other proteases. We determined that proteasome inhibitors act on rAAV through proteasome inhibition and not serine or cysteine protease inhibition, likely through positive changes late in transduction.
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Widjaja, Ivy, Erik de Vries, Donna M. Tscherne, Adolfo García-Sastre, Peter J. M. Rottier, and Cornelis A. M. de Haan. "Inhibition of the Ubiquitin-Proteasome System Affects Influenza A Virus Infection at a Postfusion Step." Journal of Virology 84, no. 18 (July 14, 2010): 9625–31. http://dx.doi.org/10.1128/jvi.01048-10.
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ABSTRACT We have demonstrated that influenza A virus (IAV) RNA synthesis depends on the ubiquitin-proteasome system. IAV replication was reduced both by proteasome inhibitors and in E36ts20 cells, which contain the thermolabile ubiquitin-activating enzyme E1. While virus entry was not affected in E36ts20 cells, the proteasome inhibitor MG132 retained viral particles in the cytoplasm. Addition-removal experiments of MG132 in combination with bafilomycin A1, a well-established inhibitor of IAV entry and fusion, showed that MG132 affected IAV infection at a postfusion step. This was confirmed by the lack of inhibition of IAV entry by proteasome inhibitors in a virus-like particle fusion assay.
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Fidor, Anna, Katarzyna Cekała, Ewa Wieczerzak, Marta Cegłowska, Franciszek Kasprzykowski, Christine Edwards, and Hanna Mazur-Marzec. "Nostocyclopeptides as New Inhibitors of 20S Proteasome." Biomolecules 11, no. 10 (October 8, 2021): 1483. http://dx.doi.org/10.3390/biom11101483.
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Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes.
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Kabore, Albert F., Kristin McCrea, James B. Johnston, and Spencer B. Gibson. "Proteasome Inhibiters Up-Regulate TRAIL/Apo2L and Its Receptors Significantly Contributing to Proteasome Inhibitor-Induced Apoptosis in Primary Chronic Lymphocytic Leukemia (CLL) Cells." Blood 104, no. 11 (November 16, 2004): 2810. http://dx.doi.org/10.1182/blood.v104.11.2810.2810.
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Abstract The proteasome inhibitor, bortezomib has recently emerged as a new therapeutic treatment for refractory multiple myeloma and is presently being evaluated for other hematological malignancies either alone or in combination with other antitumor agents. Proteasome inhibitors cause the accumulation of many proteins but the precise mechanism responsible for their antitumor effect is unclear. In the present study, we have determined that cytotoxic effect the proteasome inhibitor MG-132 in primary chronic lymphocytic leukemia (CLL) cells is through the activation of the TRAIL (tumor necrosis factor-related apoptosis inducing ligand) apoptotic pathway. MG-132 induced apoptosis in approximately 70% of primary CLL cells as measured by annexin V staining. Addition of DR4:Fc that prevents TRAIL ligation with its receptors decreased the amount of MG-132 induced apoptosis by approximately 40% suggesting MG-132 caused activation of the TRAIL apoptotic pathway. MG-132 also up-regulated both the mRNA and protein levels of TRAIL and protein levels of TRAIL receptors DR4 and DR5. This upregulation correlated with activation of caspase 8 and cleavage of pro-apoptotic Bcl-2 family member Bid. Moreover, MG-132 treatment also induced a substantial reduction in the FLICE-like inhibitory protein (c-FLIP) protein levels. In contrast to CLL cells, proteasome inhibitors failed to activate the TRAIL apoptotic pathway in normal B-cells. This indicates that proteasome inhibitors are inducing apoptosis in primary CLL cells through activation of the TRAIL apoptotic signaling pathway through up-regulation of TRAIL and its cognate receptors and reduced FLIP expression. Thus, proteasome inhibitors may have a therapeutic role in CLL, either when used alone or in combination with TRAIL or antibodies against DR4/DR5.
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Crawford, Lisa J. A., Huib Ovaa, Brian Walker, Dharminder Chauhan, Kenneth C. Anderson, Treen C. M. Morris, and Alexandra E. Irvine. "Evaluation of the Specificity and Cytotoxicity of Three Proteasome Inhibitors." Blood 106, no. 11 (November 16, 2005): 3366. http://dx.doi.org/10.1182/blood.v106.11.3366.3366.
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Abstract The proteasome is a mutlicatalytic protease with three main catalytic activities - chymotrypsin-like (CT-L), trypsin-like (T-L) and peptidylglutamyl peptide hydrolising (PGPH). Proteasome inhibition is an emerging therapy for many cancers and is a novel treatment for multiple myeloma (MM). The CT-L activity, considered to be the rate-limiting step in protein degradation, is the primary target of many proteasome inhibitors. We have compared the specificity and potency of the novel proteasome inhibitor BzLLLCOCHO to the previously characterised inhibitors PS-341 (Velcade, bortezomib) and MG-132. Specific fluorogenic substrates were used to measure proteasome proteolytic activity in the presence and absence of the inhibitory compounds. An active site directed probe with a dansyl-sulfonamidohexanoyl hapten tag was used in conjuction with immunoblotting to determine the subunit specificity of the proteasome inhibitors (Nature Methods2005;2:357–362). MM cell lines (U266, OPM-2, KMS-11, KMS-18) were incubated with 10 μM BzLLLCOCHO, 5 nM PS-341 or 1 μM MG-132 for 24 hrs and proteasome activity was measured. Addition of BzLLLCOCHO reduced CT-L activity by 83 ± 13 % in the fluorogenic assay, and T-L and PGPH activities were reduced by 93 ± 6 % and 92 ± 2 % respectively. Immunoblot results revealed a similar pattern, the T-L and PGPH subunits were completely inhibited by BzLLLCOCHO and there was only weak labeling of the CT-L subunit with the active site probe. In contrast, treatment with PS-341 completely inhibited the CT-L and PGPH activities and incubation with MG-132 resulted in weak inhibition of the CT-L and PGPH activities, neither inihibitor significantly affected T-L activity. The ability of the different inihibitors to induce apoptosis in MM cell lines was then evaluated. All three inhibitors were demonstrated to act through both the caspase-8 and caspase-9 signalling pathways. Using Mitosensor™ and Hoescht/Propidium Iodide staining we found that MM cells were more sensitive to the induction of apoptosis by PS-341 and MG-132 than BzLLLCOCHO (U266 cells treated for 72 hrs with BzLLLCOCHO 51 % apoptosis, PS-341 79 % apoptosis and MG-132 84 % apoptosis). BzLLLCOCHO is a cell permeable and potent inhibitor of all three proteolytic activities of the proteasome. PS-341 and MG-132 inhibited only two of the three proteasome activities but were more efficient than BzLLLCOCHO at inducing apoptosis in MM cell lines. MG-132 is known to inhibit non proteasomal proteases such as Cathepsin B and Calpain 1 which may contribute to its potency. Further investigation on the effects of these inhibitors on gene and protein expression in the cell may lead to the development of more specific and targeted inhibitors.
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Parlati, Francesco, Monette Aujay, Siv Lise Bedringaas, Susan Demo, Bjorn Gjertsen, Eileen Goldstein, Jing Jiang, et al. "Anti-Tumor Activity of Immunoproteasome Selective Inhibitors." Blood 110, no. 11 (November 16, 2007): 1599. http://dx.doi.org/10.1182/blood.v110.11.1599.1599.
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Abstract Background: The immunoproteasome is a form of the proteasome that is distinct from the broadly expressed constitutive proteasome. The immunoproteasome, which is predominant in hematopoetic cells, contains the unique active site subunits, LMP7, LMP2 and MECL1, accounting for the chymotrypsin-like, caspase-like and trypsin-like activity respectively. The proteasome inhibitors bortezomib and carfilzomib have validated the proteasome as a therapeutic target in hematologic malignancies; however these inhibitors target both the constitutive and immunoproteasome. We hypothesized that selective inhibition of the immunoproteasome would have anti-tumor activity on hematologic tumors and may avoid toxicities associated with constitutive proteasome inhibition. Methods: The level of immunoproteasome expression in hematologic malignant cells was not known. Hematologic tumor cell lines and primary patient samples were assessed for relative levels of immunoproteasome versus constitutive proteasome using an ELISA that quantitates proteasomal subunits. Epoxyketone-based inhibitors were generated that are >20-fold selective for the immunoproteasome subunit, LMP7, over the corresponding constitutive subunit, Beta5. Anti-tumor activity of LMP7 selective inhibitors was determined by treating tumor cell lines and primary patient cells that are predominately LMP7 expressing. Furthermore, anti-tumor effects were assessed by combining LMP7 and Beta5 inhibition using genetic and chemical methods Results: Immunoproteasome expression was variable in primary patient samples and tumor cell lines. In the majority of acute myeloid leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia patient samples, the immunoproteasome accounted for >95% of the total proteasome. In HS-Sultan, Molt4 and RL cell lines, the immunoproteasome accounted for 70%, 50% and 50% of the total proteasome, respectively. In these cell lines, complete inhibition of LMP7 was not sufficient to induce to cell death. LMP7 selective inhibitors were only cytotoxic in these cell lines under conditions where Beta5 was depleted either genetically or chemically. Genetic depletion was accomplished using Beta5-specific shRNA expression in HS-Sultan, Molt4 and RL cells which increased the relative LMP7 levels to 95%, 80% and 70% respectively. These cells were significantly more sensitive to LMP7 inhibition than their parental cells, suggesting that cell kill requires suppression of LMP7 and Beta5. Chemically, combinations of Beta5 and LMP7 selective inhibitors showed similar results, i.e. greater cytotoxicity in combination than either inhibitor alone. Acute lymphocytic leukemia patient samples were screened for LMP7 expression and anti-tumor activity of the LMP7 selective inhibitors correlated with the relative levels of LMP7 expression. Conclusion: This work suggests that tumor cells with high relative levels of LMP7 will be sensitive to LMP7 selective inhibition. These results support the development of immunoproteasome-selective inhibitors for the treatment of hematologic malignancies where high levels of immunoproteasome expression are observed. An LMP7 selective inhibitor has been identified as a clinical candidate for development in leukemia.
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Kirk, Christopher J., Monette A. Aujay, Mark Ho, Jing Jiang, Guy J. Laidig, Evan R. Lewis, Yan Lu, et al. "Pharmacologic Evaluation of Orally Bioavailable Inhibitors of the 20S Proteasome." Blood 108, no. 11 (November 16, 2006): 3581. http://dx.doi.org/10.1182/blood.v108.11.3581.3581.
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Abstract Clinical application of proteasome inhibitors in the treatment of hematologic malignancies such as myeloma and lymphoma is restricted in part by the necessity of frequent IV administration and would be improved by oral (PO) administration. Selective inhibitors of the protease subunits of the 20S proteasome can be generated from peptidyl aldehydes, boronates, vinyl sulfones, and epoxyketones. Many of these peptide based proteasome inhibitors are cell permeant and capable of systemic proteasome inhibition upon intravenous (IV) administration to experimental animals such as mice and rats. In the cases of the peptidyl boronate bortezomib (Velcade™) and the epoxyketone PR-171, proteasome inhibition can be achieved in patients with IV administration. However, systemic exposure following PO administration of these inhibitors may be limited by several factors including gastric pH, gastric and intestinal peptidases, efflux pumps, biliary excretion and intestinal and hepatic metabolic activities. We have tested over 80 peptide epoxyketones with potent (IC50 <100 nM) in vitro inhibitory activity against the chymotrypsin-like activity of the 20S proteasome for bioavailability following PO administration in mice. Systemic exposure was monitored by measuring chymotrypsin-like inhibition in a number of tissues and an approximation of the relative bioavailability for selected compounds was measured by comparing the pharmacodynamics of IV and PO administration using a range of doses. These compounds were also tested in vitro for solubility, intestinal cell permeability, intestinal and hepatic metabolism, and sensitivity to the multidrug resistance protein 1 (MDR1) efflux pump in order to determine which properties were associated with oral bioavailability. We have found that oral bioavailability in mice is associated with increased intrinsic solubility and metabolic stability and reduced MDR1 sensitivity. Proteasome inhibition following PO administration is rapid, resulting in maximal proteasome inhibition within 15 minutes. Rapid absorption and clearance of selected compounds was also confirmed in mice and rats by pharmacokinetic analysis. Repeated oral administration was well tolerated at doses that resulted in significant (>80%) proteasome inhibition in most tissues. The anti-tumor efficacy of these orally bioavailable proteasome inhibitors are being assessed in both human tumor xenograft and mouse syngeneic models. The results from these studies will enable further pre-clinical development of potent, orally bioavailable proteasome inhibitors for the treatment of malignant diseases.
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Harding, C. V., J. France, R. Song, J. M. Farah, S. Chatterjee, M. Iqbal, and R. Siman. "Novel dipeptide aldehydes are proteasome inhibitors and block the MHC-I antigen-processing pathway." Journal of Immunology 155, no. 4 (August 15, 1995): 1767–75. http://dx.doi.org/10.4049/jimmunol.155.4.1767.
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Abstract Class I MHC (MHC-I) molecules present peptides derived from Ag that are processed in the cytosol. The proteasome is a multicatalytic protease complex that is present in the cytosol and has been implicated in cytosolic Ag processing. Novel dipeptide aldehydes were designed, synthesized, and demonstrated to specifically inhibit the chymotrypsin-like protease activity of isolated proteasomes, but produced relatively little inhibition of cathepsin B, a vacuolar cysteine protease. The inhibitors were membrane permeable and inhibited intracellular cleavage of a membrane-permeable fluorogenic substrate of the chymotrypsin-like proteasome activity. When a model Ag, OVA, was introduced into the cytoplasm of M12.B6 murine B cells by electroporation, the proteasome inhibitors blocked its processing for subsequent presentation by MHC-I molecules. The inhibitors had little effect on class II MHC processing of exogenous Ag. The potencies of different inhibitors for blockade of MHC-I Ag processing correlated directly with their potencies for inhibition of the chymotrypsin-like proteasome activity. In contrast, conventional inhibitors of vacuolar cysteine proteases (e.g., leupeptin and benzyloxycarbonyl-Phe-Ala-CHN2) had little effect on MHC-I processing or the chymotryspin-like activity of isolated proteasomes. These results directly demonstrate that inhibition of proteasome activity blocks MHC-I Ag processing, confirming a role for proteasomes in this pathway. Moreover, they suggest that the chymotrypsin-like activity of the proteasome may be of major importance to the cytosolic processing of at least some Ag.
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Sha, Zhe, Helena M. Schnell, Kerstin Ruoff, and Alfred Goldberg. "Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation." Journal of Cell Biology 217, no. 5 (March 13, 2018): 1757–76. http://dx.doi.org/10.1083/jcb.201708168.
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Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions.
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Kraus, Marianne, Bobby Florea, Jürgen Bader, Nan Li, Paul Geurink, Wouter van der Linden, Hermen S. Overkleeft, and Christoph Driessen. "Selective Inhibition of the proteasome's β2 Catalytic Subunit Alone Does Not Induce Cytotoxicity, but Resensitizes Bortezomib-Refractory Myeloma Cells for Bortezomib Treatment." Blood 118, no. 21 (November 18, 2011): 2915. http://dx.doi.org/10.1182/blood.v118.21.2915.2915.
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Abstract Abstract 2915 Bortezomib is a reversible first-generation proteasome inhibitor that inhibits the β5 and to a lesser extent the β1 catalytic site of the proteasome. However, bortezomib does not inhibit the β2 catalytic proteasomal site at clinically relevant concentrations, and bortezomib-resistance is accompanied by upregulation of the β2 subunit, suggesting that increased β2 activity may compensate for the loss of β1/ β5 activity during bortezomib-treatment. The second generation proteasome inhibitor carfilzomib, due to the chemistry of its epoxyketone warhead, has a higher substrate specificity and functions as an irreversible proteasome inhibitor, but is still a β1/ β5 inhibitor that does not affect the β2 active site. We investigated the effect of β2-specific proteasome inhibition on myeloma and acute myeloid leukemia (AML) cells and tested the hypothesis that β2-selective proteasome inhibition may overcome bortezomib-resistance. To this end we have developed a set of epoxyketone- and vinylsulfone-based, cell permeable proteasome inhibitors of which we selected the compounds PR523A and PR671A for further testing in cell-based assays. PR671A is a peptide-vinylsulfone that selectively inhibits the proteasome's β2/ β2i subunit in an irreversible fashion in human cell lines and primary cells at low micromolar concentrations without inhibition of other protease species. PR523A is a β5-selective peptide-epoxyketone with otherwise similar properties. Treatment of myeloma and AML cell lines (AMO-1, U-266, HL-60, THP-1) with PR523A induced ER-stress mediated apoptosis, very similar to bortezomib. The combination of bortezomib with PR523A led to additive, but not synergistic induction of apoptosis, as expected. Selective β2 inhibition by PR671A resulted in the induction of ER stress and the accumulation of poly-ubiquitinated protein, however, this was not effectively translated into apoptotic cell death. This indicates that selective inhibition of the β2 proteasome subunit alone has only a poor cytotoxic effect on myeloma and AML cell lines, suggesting that the function of β2 is largely redundant and can be compensated when the remaining proteasome catalytic subunits (β1 and β5) remain active. However, when the β2 inhibitor PR671A was combined with agents that target the proteasome's β5 active site (PR523A) or the β5 and the β1 site (bortezomib), the combination of either inhibitor with the β2 inhibitor PR671A was highly synergistic for both activation of ER stress and the induction of apoptotic death. Importantly, the bortezomib-resistance in bortezomib-adapted myeloma and AML cell lines could be overcome by combining PR671A with either bortezomib or PR523A, while β2 inhibition by PR671A alone had no effect on the viability of bortezomib-adapted cells. We conclude that PR671A is a β2 selective proteasome inhibitor. Selective Inhibition of the proteasome's β2 subunit has little effect on viability or ER stress both in normal and bortezomib-resistant myeloma and leukemia cells, suggesting that the function of the β2 catalytic site is largely redundant. However, when β1/ β5 proteasome activity is inhibited by drugs like bortezomib or carfilzomib, proper function of the β2 proteasome active site is crucial for cell survival, also in bortezomib-resistant myeloma cells. The use of specific β2 inhibitors like PR671A in combination with β1/ β5 inhibitors like bortezomib or carfilzomib is therefore a promising strategy to overcome resistance against β1/ β5-selective proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "Proteasome-like inhibitors"
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Burns, Amy Lee. "Investigation of azithromycin analogues and proteasome-like inhibitors as quick-killing antimalarials." Thesis, 2019. http://hdl.handle.net/2440/123090.
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Malaria is caused by mosquito-borne parasites of the genus Plasmodium which were responsible for ~435,000 of deaths annually, with >90% caused by the deadliest species, P. falciparum. Over the last two decades, global implementation of vector control and artemisinin combination therapies have resulted in significant reductions in the global burden of malaria. Of current concern is the spread of multi-drug resistant parasites that have severely limited the efficacy of antimalarials, including front-line artemisinins, highlighting the urgent need to identify new antimalarials for use as treatments. The aim of this thesis was to investigate novel antimalarial development avenues and identify new chemotypes that could be used in the near future as treatments. The macrolide antibiotic azithromycin is known to target the malaria parasites remnant plastid organelle (the apicoplast’s) bacterial-like ribosome and causes slow-killing ‘delayed death’, where the parasite dies in the second replication cycle (4 days). Azithromycin has also been shown to inhibit invading merozoites and kill blood stages within the first replication cycle (2 days) via an unidentified mechanism, proposed to be independent of delayed death. Thus, we hypothesised that azithromycin could be redeveloped into an antimalarial with two different mechanisms of action against parasites: delayed death and quick-killing. Over 100 azithromycin analogues that featured a high proportion of different structural profiles were obtained, leading to improved quick-killing activities over azithromycin. Quick-killing was also confirmed to be completely unrelated to delayed death, as blood stage parasites lacking the apicoplast were equally susceptible to quick-killing of azithromycin and analogues. Two different avenues were also confirmed for azithromycin’s antimalarial re-development: delayed death and quick-killing or quick-killing only, which could be modulated depending on the location of added functional groups. Azithromycin and analogues were found to be active across blood stage development, with only short treatments required to kill parasites. The metabolomics signatures of parasites treated with azithromycin and analogues suggested that quick-killing acts multi-factorially, with the parasite’s food vacuole and mitochondria being likely targets. Finally, in vitro activities of two subtypes of tri-peptide proteasome-like inhibitors, vinyl sulfone and aldehydes, were addressed against P. falciparum and the zoonotic malaria parasite P. knowlesi. All compounds exhibited low-nanomolar activities against both Plasmodium spp. and showed excellent selectivity for parasites over human cells, suggesting these inhibitors provide viable chemical scaffolds for optimisation. There was no evidence of increased protein ubiquitination upon treating parasites with these compounds, suggesting they do not target the proteasome. We also investigated whether hypoxia inducible pro-drug proteasome-like inhibitors could be used to reduce host toxicity of antimalarials. However, these pro-drugs could be not activated in in vitro culture conditions and there was limited evidence suggesting this strategy would be applicable in malaria. These studies build on previous findings on the drug-killing efficacy, mechanism of action and possible application of redeveloping azithromycin analogues as new and improved antimalarials. I also identified new proteasome inhibitor-like scaffolds as starting points for further development. This body of work provides thorough biological characterisation of a panel of compounds that could lead to new avenues for antimalarial development.Thesis (Ph.D.) -- University of Adelaide, School of Biololgical Sciences, 2020
Book chapters on the topic "Proteasome-like inhibitors"
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Chen, Linlin, Hong Zhang, Mengyi Chi, Quanjun Yang, and Cheng Guo. "Drugs for the Treatment of Muscle Atrophy." In Background and Management of Muscular Atrophy. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.93503.
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Muscle mass is maintained through an interplay between anabolic and catabolic pathways. The ubiquitin-proteasome system plays an important role in the proteolysis progress during skeletal muscle atrophy which can be blocked by some proteasome inhibitors. But few studies have demonstrated the ability of these inhibitors to preserve muscle mass and architecture under catabolic condition in vivo. The insulin-like growth factor-1/phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway was associated with anabolic pathways. The activation of IGF-1 causes muscle hypertrophy; however, it cannot be used as a drug target. Myostatin pathway maintains activation that can induce skeletal muscle atrophy involved with various transcriptional and genetic factors. Skeletal muscle atrophy is a debilitating consequence of multiple chronic diseases and conditions that involve starvation. It reduces treatment options and positive clinical outcomes as well as compromising quality of life and increasing morbidity and mortality. Though considerable research has been undertaken to find the drug target and the molecular mechanisms that improve skeletal muscle atrophy, no drug was approved to treat skeletal muscle atrophy. However, these years, the signaling pathways involved in muscle atrophy were clarified and some effective treatments were currently available to prevent, attenuate, or reverse muscle atrophy for experiment research.
Conference papers on the topic "Proteasome-like inhibitors"
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Ge, Yiyu, Sevil Ozcan, Aslamuzzaman Kazi, Frank Marsilio, Kenyon Daniel, Wesley Brooks, Wayne Guida, Harshani Lawrence, and Said Sebti. "Abstract 1362: Discovery of a novel structural class of compounds: HLM-030376 and its analogs as potent chymotrypsin-like proteasome inhibitors." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-1362.
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