A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. We attached an electrophile to 100 fragments without significant alterations in the reactivity of the electrophile. A mass spectrometry assay discovered three nonpeptidic inhibitors of the cysteine protease papain. The identified compounds display the characteristics...

A series of protease inhibitors were tested on the motility of human, rat, bull, and rabbit demembranated reactivated spermatozoa. Some inhibitors, including aprotinin, boc-gln-leu-lys-H, and D-phe-pro-arg-H, could inhibit motility as well as prevent initiation of motility. In general, with the exception of aprotinin, protease inhibitors were more potent in preventing the initiation of movement...

Chemotactic chemokines can be released from lung fibroblasts in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. An imbalance between proteases and antiproteases has been observed at inflammatory sites, and, therefore, protease inhibitors might modulate fibroblast release of chemotactic cytokines. To test this hypothesis, serine protease inhibitors (FK-706, alpha(1)-ant...

background: proteolytic enzymes have an important role in variety of physiological and pathological functions. they have been used in therapeutic and pharmaceutical applications. characterizations of extracellular proteases from various strains of s. marcescens indicate that most strains produce a very similar major metalloprotease. this metalloprotease (serrapeptidase, serrapeptase) is an impo...

Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the imp...

The advent of highly active antiretroviral therapy (HAART), including the use of HIV protease inhibitors (PIs) has significantly reduced the morbidity and mortality of AIDS in HIV infected patients. Unfortunately, the adverse effects of PIs, including dyslipidemia, lipodystrophy, insulin resistance, and premature atherosclerosis, are cause for concern for their use in chronic management of HIV ...

HIV protease inhibitors must penetrate into cells to exert their action. Differences in the intracellular pharmacokinetics of these drugs may explain why some patients fail on therapy or suffer from drug toxicity. Yet, there is no information available on the intracellular levels of HIV protease inhibitors in HIV infected children, which is in part due to the large amount of sample that is norm...

OBJECTIVE The aim of this study is to assess the effectiveness of continuous regional arterial infusion (CRAI) of protease inhibitors in patients with severe acute pancreatitis (SAP) including acute necrotizing pancreatitis. METHODS This retrospective study was conducted among 44 institutions in Japan from 2009 to 2013. Patients 18 years or older diagnosed with SAP according to the criteria o...