Cysteine Endopeptidases

Publication Title: 
Annals of the New York Academy of Sciences

Aging is characterized by accumulation of potentially harmful altered proteins that could lead to gradual deterioration of cellular functions and eventually result in increased probability of death. Metabolic turnover of proteins thus plays an essential role in maintaining the life of an organism. In this article we summarize our current knowledge on age-related changes in protein turnover with special reference to degradation. Increase in half-life of proteins with advancing age is well documented.

Author(s): 
Goto, S.
Takahashi, R.
Kumiyama, A. A.
Rad·k, Z.
Hayashi, T.
Takenouchi, M.
Abe, R.
Publication Title: 
Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica

AIM: To study the effect of artemether (Art) on the thio proteinase ("hemoglobinase", Hem) of Schistosoma japonicum. METHODS: Hem was extracted from S japonicum adults. The inhibitory effect of Art on the activity of Hem to degrade human hemoglobin (Hgb) was examined with UV-photometer at 280 nm, SDS-PAGE and scanning at 600 nm on a chromoscanner. RESULTS: Human Hgb was degraded at pH 4.0 by the Hem. The activities of Hem preincubated at 37 degrees C with Art 0.14, 1.4, and 14 mmol.L-1, were inhibited by 30.2%, 39.8%, and 45.0%, respectively.

Author(s): 
Gong, P. L.
Li, Y. L.
Feng, Y. R.
Publication Title: 
Bioorganic & Medicinal Chemistry Letters

A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.

Author(s): 
Capela, Rita
Oliveira, Rudi
Gonçalves, Lídia M.
Domingos, Ana
Gut, Jiri
Rosenthal, Philip J.
Lopes, Francisca
Moreira, Rui
Publication Title: 
Molecules (Basel, Switzerland)

The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC(50) values in the 0.29-10.63 ?M range.

Author(s): 
Liu, Yang
Cui, Kunqiang
Lu, Weiqiang
Luo, Wei
Wang, Jian
Huang, Jin
Guo, Chun
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations.

Author(s): 
Klonis, Nectarios
Crespo-Ortiz, Maria P.
Bottova, Iveta
Abu-Bakar, Nurhidanatasha
Kenny, Shannon
Rosenthal, Philip J.
Tilley, Leann
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Malaria parasites use hemoglobin (Hb) as a major nutrient source in the intraerythrocytic stage, during which heme is converted to hemozoin (Hz). The formation of Hz is essential for parasite survival, but to date, the underlying mechanisms of Hb degradation and Hz formation are poorly understood. We report the presence of a ?200-kDa protein complex in the food vacuole that is required for Hb degradation and Hz formation. This complex contains several parasite proteins, including falcipain 2/2', plasmepsin II, plasmepsin IV, histo aspartic protease, and heme detoxification protein.

Author(s): 
Chugh, Monika
Sundararaman, Vidhya
Kumar, Saravanan
Reddy, Vanga S.
Siddiqui, Waseem A.
Stuart, Kenneth D.
Malhotra, Pawan
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

The formation of polyglutamine-containing aggregates and inclusions are hallmarks of pathogenesis in Huntington's disease that can be recapitulated in model systems. Although the contribution of inclusions to pathogenesis is unclear, cell-based assays can be used to screen for chemical compounds that affect aggregation and may provide therapeutic benefit. We have developed inducible PC12 cell-culture models to screen for loss of visible aggregates.

Author(s): 
Apostol, Barbara L.
Kazantsev, Alexsey
Raffioni, Simona
Illes, Katalin
Pallos, Judit
Bodai, Laszlo
Slepko, Natalia
Bear, James E.
Gertler, Frank B.
Hersch, Steven
Housman, David E.
Marsh, J. Lawrence
Thompson, Leslie Michels
Publication Title: 
American Journal of Physiology. Gastrointestinal and Liver Physiology

The inflammatory response during pancreatitis regulates necrotic and apoptotic rates of parenchymal cells. Neutrophil depletion by use of anti-polymorphonuclear serum (anti-PMN) increases apoptosis in experimental pancreatitis but the mechanism has not been determined. Our study was designed to investigate signaling mechanisms in pancreatic parenchymal cells regulating death responses with neutrophil depletion. Rats were neutrophil depleted with anti-PMN treatment. Then cerulein pancreatitis was induced, followed by measurements of apoptosis signaling pathways.

Author(s): 
Nakamura, Yuji
Do, Jae Hyuk
Yuan, Jingzhen
Odinokova, Irina V.
Mareninova, Olga
Gukovskaya, Anna S.
Pandol, Stephen J.
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