Characterization and Optimization of Selective, Nonpeptidic Inhibitors of Cathepsin S with an Unprecedented Binding Mode

Inagaki, Hiroaki; Tsuruoka, Hiroyuki; Hornsby, Michael; Lesley, Scott A.; Spraggon, Glen; Ellman, Jonathan A.

doi:10.1021/jm070111+

Cited by 24 publications

(18 citation statements)

References 16 publications

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“…We therefore applied a substrate-based fragment approach called substrate activity screening (SAS) to the development of nonpeptidic inhibitors of caspases-3 and -6. In the SAS method, which has previously been applied to proteases of the papain family, (Brak et al, 2008; Inagaki et al, 2007; Patterson et al, 2006; Wood et al, 2005) weak binding nonpeptidic substrate fragments are identified, optimized, and then converted to potent inhibitors. Herein, we report the identification of three novel, nonpeptidic pan-caspase irreversible inhibitors that blocked proteolysis of Htt at caspase-3 and caspase-6 sites, suppressed Hdh 111Q/111Q -mediated toxicity, and rescued HttN90Q73-induced degeneration of rat striatal and cortical neurons.…”

Section: Introductionmentioning

confidence: 99%

Identification and Evaluation of Small Molecule Pan-Caspase Inhibitors in Huntington's Disease Models

Leyva

DeGiacomo

Kaltenbach

et al. 2010

Chemistry & Biology

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SUMMARY Huntington’s Disease (HD) is characterized by a mutation in the huntingtin gene encoding an expansion of glutamine repeats on the N-terminus of the huntingtin (Htt) protein. Numerous studies have identified Htt proteolysis as a critical pathological event in post mortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD targets. We report the use of the substrate activity screening method against caspases-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models, these irreversible inhibitors suppressed Hdh111Q/111Q-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.

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Section: Introductionmentioning

confidence: 99%

Identification and Evaluation of Small Molecule Pan-Caspase Inhibitors in Huntington's Disease Models

Leyva

DeGiacomo

Kaltenbach

et al. 2010

Chemistry & Biology

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“…They have led to the identification of active substrates and the subsequent optimization of inhibitors for cruzaine (also known as cruzipain)49, a cysteine protease of Trypanosoma cruzi that is the causative agent of Chagas disease. Also, inhibitors of cathepsin S 50, which is implicated in autoimmune diseases, and inhibitors of the hepatitis C virus protease51 have been identified. Positional scanning methods and complete platforms for inhibitor screening were also developed for screening MMPs.…”

Section: Protease Inhibitor Drug Discoverymentioning

confidence: 99%

Emerging principles in protease-based drug discovery

Drąg

Salvesen

2010

Nat Rev Drug Discov

507

458

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Proteases have an important role in many signalling pathways, and represent potential drug targets for diseases ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses. Although inhibitors of well-established protease targets such as angiotensin-converting enzyme and HIV protease have shown substantial therapeutic success, developing drugs for new protease targets has proved challenging in recent years. This in part could be due to issues such as the difficulty of achieving selectivity when targeting protease active sites. This Perspective discusses the general principles in protease-based drug discovery, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets.Proteins are among the most stable biological polymers. Peptide bonds can withstand hours in boiling concentrated acid, yet they last no more than microseconds in the presence of a specific protease. The study of proteolysis goes back at least to the nineteenth century with the description of pepsin by Schwann in 1836 and of trypsin by Corvisart in 1856. Since then, proteases have been identified in almost every organism, have been discovered to play a part in most biological pathways 1 and have been implicated in almost every disease.Historically, much of the focus has been on the role of proteases in coagulopathies, inflammation, infectious diseases, cancer and degenerative diseases, and some protease inhibitors have been developed into highly successful drugs. For example, inhibitors of the human protease angiotensin-converting enzyme (ACE), such as captopril, have been used in the treatment of cardiovascular disorders, primarily hypertension and congestive heart failure, for several decades 2 . In addition, inhibitors of the HIV protease, such as ritonavir, atazananvir and tipranavir (Aptivus; Pfizer/Boehringer Ingelheim), have had a key role in transforming the treatment of HIV infection since their introduction in the mid-1990s 3 (see TABLE 1 Published in final edited form as:Nat Rev Drug Discov. 2010 September ; 9(9): 690-701. doi:10.1038/nrd3053. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sales of US$1 billion, which is anticipated to rise to $3.5 billion by 2014 (REF. 4 ), whereas antihypertensive drugs that act on the proteases in the renin-angiotensin system currently have over $6 billion global sales 1 . Indeed, at present, we estimate that 5-10% of all pharmaceutical targets being pursued for drug development are proteases.The general strategy for therapeutically targeting proteases is to identify a specific inhibitor -generally a small molecule -that blocks the active site. As discussed below, discovery efforts for new inhibitors have typically been based on the structure of known protease substrates, presenting a substantial challenge for the development of peptidomimetic compounds that have the pharmacokinetic characteristics needed to be sui...

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“…To overcome the stability issues of peptidic inhibitors, we screened several recently reported non-peptidic scaffolds from a large library of compounds that was initially designed to target cysteine cathepsins in mammals (Brak et al, 2008; Brak et al, 2010; Inagaki et al, 2007; Patterson et al, 2006; Wood et al, 2005). These inhibitors use a 2,3,5,6-tetrafluorophenoxyarylmethyl ketone (TFPAMK) reactive group, and the P1 and P2 residues are linked through a triazole ring (see Table 1 for structures).…”

Section: Resultsmentioning

confidence: 99%

Functional Studies of Plasmodium falciparum Dipeptidyl Aminopeptidase I Using Small Molecule Inhibitors and Active Site Probes

Deu

Leyva

Albrow

et al. 2010

Chemistry & Biology

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100

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SUMMARY The widespread resistance of malaria parasites to all affordable drugs has made the identification of new targets urgent. Dipeptidyl aminopeptidases (DPAPs) represent potentially valuable new targets that are involved in hemoglobin degradation (DPAP1) and parasite egress (DPAP3). Here we use activity-based probes to demonstrate that specific inhibition of DPAP1 by a small molecule results in the formation of an immature trophozoite that leads to parasite death. Using computational methods we designed stable, non-peptidic covalent inhibitors that kill Plasmodium falciparum at low nanomolar concentrations. These compounds show signs of slowing parasite growth in a murine model of malaria, which suggests that DPAP1 might be a viable anti-malarial target. Interestingly, we found that re-synthesis and activation of DPAP1 after inhibition is rapid, suggesting that effective drugs would need to sustain DPAP1 inhibition for a period of 2–3h.

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Characterization and Optimization of Selective, Nonpeptidic Inhibitors of Cathepsin S with an Unprecedented Binding Mode

Cited by 24 publications

References 16 publications

Identification and Evaluation of Small Molecule Pan-Caspase Inhibitors in Huntington's Disease Models

Identification and Evaluation of Small Molecule Pan-Caspase Inhibitors in Huntington's Disease Models

Emerging principles in protease-based drug discovery

Functional Studies of Plasmodium falciparum Dipeptidyl Aminopeptidase I Using Small Molecule Inhibitors and Active Site Probes

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