Cysteine proteases of parasitic organisms☆

Sajid, Mohammed; McKerrow, James H.

doi:10.1016/s0166-6851(01)00438-8

Cited by 720 publications

(612 citation statements)

References 102 publications

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“…In babesipain-1, as in other enzymes of the family, Gln19 and Trp179, whose side chains form the ''oxyanion hole'', are in a similar orientation (Fig. 6a); this is an important feature for the enzyme's proteolytic activity, as the ''oxyanion hole'' stabilizes the tetrahedral adduct during the nucleophilic attack of the thiolate anion to the appropriate electron deficient carbonyl of the substrate [32]. Additionally, we observed the typical glycine-rich region, comprising mainly Gly65 and Gly66, that in other papain-like cysteine proteases was found to provide additional stability to the complex by forming a constellation of hydrogen bonds with the substrate [39].…”

Section: Babesipain-1 Structurementioning

confidence: 95%

“…Alignment of babesipain-1 with the selected templates showed strict conservation of the catalytic residues, and low polymorphism in their surrounding areas. Notably, the tryptophan (Trp179) that forms the ''oxyanion hole'' together with Gln19 is also preserved [32], and other additional structurally conserved regions are observed, thus making the selected hits suitable templates.…”

Section: Template Selection and Sequence Alignmentmentioning

confidence: 99%

“…Usually, the active site of papain-like cysteine proteases is constituted by four pockets [32], S1, S1 0 , S2 and S3, as shown in Fig. 7.…”

Section: Babesipain-1 Structurementioning

confidence: 99%

“…As previously reported, these differences are observed mainly in the S2 site [6], while cavity S1 is more conserved. The nature of the S2 pocket, and in particular of the residue present in the hollow end of the pocket, is thought to be essential to the substrate specificity of clan CA enzymes [32]. Hydrophobic residues usually constitute the S2 pocket, but the key residue (residue 205 in papain) present at the bottom of the pocket is not conserved [32].…”

Section: Babesipain-1 Structurementioning

confidence: 99%

“…The nature of the S2 pocket, and in particular of the residue present in the hollow end of the pocket, is thought to be essential to the substrate specificity of clan CA enzymes [32]. Hydrophobic residues usually constitute the S2 pocket, but the key residue (residue 205 in papain) present at the bottom of the pocket is not conserved [32]. In this critical position of falcipain-2 and of babesipain-1, we find the polar residue Asp234 [40] and the bulky hydrophobic Phe206 residue, respectively.…”

Section: Babesipain-1 Structurementioning

confidence: 99%

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Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies

Pérez

Antunes

Gonçalves

et al. 2013

J Comput Aided Mol Des

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Babesia bigemina is a protozoan parasite that causes babesiosis, a disease with a world-wide distribution in mammals, principally affecting cattle and man. The unveiling of the genome of B. bigemina is a project in active progress that has already revealed a number of new targets with potential interest for the design of anti-babesiosis drugs. In this context, babesipain-1 has been identified as a proteolytically active enzyme whose three-dimensional structure has not been resolved yet, but which is known to be inhibited by cysteine proteases inhibitors such as E64, ALLN, leupeptin, and vinyl sulfones. In this work, we introduce (1) a homology model of babesipain-1; (2) a comparison between babesipain-1 and falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum; (3) in vitro data for babesipain-1 inhibition by HEDICINs and HECINs, previously reported as modest inhibitors of falcipain-2; and (4) the docked binding conformations of HEDICINs and HECINs in the model of babesipain-1. HEDICINs presented similar preferred binding conformations for both babesipain-1 and falcipain-2. However, in vitro bioassay shows that HEDICINs and HECINs are better inhibitors of babesipain-1 than of falcipain-2, which could be explained by observed differences between the active pockets of these proteins in silico. Results presented herein provide a valuable contribution to future computer-aided molecular design of new babesipain-1 inhibitors.

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Section: Babesipain-1 Structurementioning

confidence: 95%

Section: Template Selection and Sequence Alignmentmentioning

confidence: 99%

“…Usually, the active site of papain-like cysteine proteases is constituted by four pockets [32], S1, S1 0 , S2 and S3, as shown in Fig. 7.…”

Section: Babesipain-1 Structurementioning

confidence: 99%

Section: Babesipain-1 Structurementioning

confidence: 99%

Section: Babesipain-1 Structurementioning

confidence: 99%

See 3 more Smart Citations

Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies

Pérez

Antunes

Gonçalves

et al. 2013

J Comput Aided Mol Des

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Engineering Resistance to Insect Pests

Ferry

Edwards

Mulligan

et al. 2004

Handbook of Plant Biotechnology

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With a projected increase in world population to 10 billion over the next four decades, an immediate priority for agriculture is to achieve maximum production of food and other products in a manner which is environmentally sustainable and cost effective. Despite the synthesis of improved pesticides, and integrated pest management strategies, yield losses due to insects have actually increased slightly for most crops over the last two decades. The concept of utilising a transgenic approach to host plant resistance was realised in the mid 1990s with the commercial introduction of genetically modified crops expressing genes encoding the entomocidal d‐endotoxin from Bacillus thuringiensis ( Bt ). More recently this strategy has been extended to include the pyramiding (stacking) of genes encoding different Bt toxins for greater levels of pest control. Although not as yet a commercial reality, other strategies based on the use of plant derived genes (enzyme inhibitors, lectins) and those from animal sources, including insects (biotin‐binding proteins, neurohormones, enzyme inhibitors), are being developed. The use of fusion proteins to increase the spectrum and durability of resistance is also actively being pursued. However, if transgenic insect‐resistant crops are to play a useful role in crop protection, it is apparent that they must be compatible with the other components of integrated pest management (IPM). The current chapter addresses the role of insect‐resistant transgenic crops in agriculture and discusses both their current status and future developments. Given the importance of natural enemies in controlling pest populations, the potential impact of such crops on predators and parasitoids is also addressed.

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Antiprotozoal Agents

Friès¹,

Fairlamb²

2003

Burger's Medicinal Chemistry and Drug Discovery

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The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against T. brucei gambiense . Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in in vivo preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the N 1 , N 8 ‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.

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Cysteine proteases of parasitic organisms☆

Cited by 720 publications

References 102 publications

Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies

Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies

Engineering Resistance to Insect Pests

Antiprotozoal Agents

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