Non-Peptidic Inhibitors of Cysteine Proteases

Schirmeister, Tanja; Kaeppler, Ulrich

doi:10.2174/1389557033488079

Cited by 31 publications

(22 citation statements)

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“…As far as nonpeptide FP inhibitors are concerned (Fig. 9), these include chalcones [108], which are biosynthetic precursors of flavonoids, isoquinolines [95,96] and thiosemicarbazones [109].…”

Section: Falcipain Inhibitors: Potential Antimalarial Drugsmentioning

confidence: 99%

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Teixeira¹,

Gomes²,

Gomes

2011

CMC

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There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria.Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.

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Section: Falcipain Inhibitors: Potential Antimalarial Drugsmentioning

confidence: 99%

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Teixeira¹,

Gomes²,

Gomes

2011

CMC

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“…78,111 This class of inhibitors has been tested against several types of proteases, including serine proteases, aspartyl proteases, and metalloproteases, but they are irreversible and selective inhibitors of cysteine proteases. 112 Further aziridines, such as aziridine-2-carboxylates and aziridine-2,3-dicarboxylates, are hydrolyzed by serine proteases.…”

Section: E Peptidyl Aziridinesmentioning

confidence: 99%

Falcipain‐2 inhibitors

Ettari

Bova

Zappalà

et al. 2009

Medicinal Research Reviews

132

106

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Malaria, particularly that one caused by Plasmodium falciparum, remains a serious health problem in Africa, South America, and many parts of Asia where it afflicts about 500 million people and is responsible for the death of more than one million children each year. The main reasons for the persistence of malaria are the emergence of resistance to common antimalarial drugs, inadequate control of mosquito vectors, and the lack of effective vaccines. Therefore, the identification and characterization of new targets for antimalarial chemotherapy are of urgent priority. This review is focused on inhibitors of falcipain-2, a cysteine protease from P. falciparum, which represents one of the most promising targets for antimalarial drug design. Falcipain-2 is a key enzyme in the life cycle of P. falciparum since it degrades hemoglobin, at the early trophozoite stage, and cleaves ankyrin and protein 4.1, the cytoskeletal elements vital to the stability of red cell membrane, at the schizont stage. The main classes of falcipain-2 inhibitors are peptides or peptidomimetics bearing the most popular pharmacophores of cysteine protease inhibitors, such as vinyl sulfones, halomethyl ketones, and aldehydes. Furthermore, many other chemotypes have been identified as inhibitors of falcipain-2, such as isoquinolines, thiosemicarbazones, and chalcones. These inhibitors represent all classes, which, to the best of our knowledge, have been disclosed in journal articles to date.

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“…Different classes of the reversible and irreversible protease inhibitors discovered through these efforts are described in Schirmeister and Kaeppler. 10 Screening of a protease-focused li-brary that we have assembled from our internal collection of more than 650,000 compounds yielded several new classes of smallmolecule caspase-3 inhibitors. In this report, we describe mechanistic and selectivity profiles of a new series of potent nonpeptide inhibitors, as well as their cell-based and zebrafish antiapoptotic action.…”

Section: Caspases Are Found Practically In All Organisms Frommentioning

confidence: 99%

Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

Okun

Malarchuk²,

Dubrovskaya³

et al. 2006

SLAS Discovery

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From the authors'650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and antiapoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC 50 = 130 nM), was reversible though noncompetitive, and had a broad selectivity profile to other caspases belonging to groups I to III. The compound was effective in preventing staurosporineinduced apoptosis in a few cell lines and retinoic acid-induced apoptosis in zebrafish. (Journal of Biomolecular Screening 2006:277-285)

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Non-Peptidic Inhibitors of Cysteine Proteases

Cited by 31 publications

References 1 publication

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Falcipain‐2 inhibitors

Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

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