Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates

Royo, Santiago; Schirmeister, Tanja; Kaiser, Marcel; Jung, Sascha; Rodrı́guez, Santiago; Bautista, José M.; González, Florenci V.

doi:10.1016/j.bmc.2018.07.015

Cited by 33 publications

(38 citation statements)

References 25 publications

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“…In recent years, several classes of peptide molecules have been found to exhibit good inhibitory activity against CPs . One of the most studied groups of inhibitors of this family of enzymes are the vinyl sulfones, which have demonstrated efficacy in preclinical trials .…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, several classes of peptide moleculesh ave been found to exhibit good inhibitory activity against CPs. [7][8][9][10][11][12][13][14] One of the most studied groups of inhibitors of this family of enzymes are the vinyl sulfones,w hich have demonstrated efficacy in preclinical trials. [8] For instance, the vinyl sulfone Nmethylpiperazine-Phe-homoPhe-vinylsulfone-phenyl (K11777) protects dogs from cardiac damage during infection by Trypanosoma cruzi.…”

Section: Introductionmentioning

confidence: 99%

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Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes

Arafet

González

Moliner

2020

Chemistry A European J

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In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free‐energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β‐carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes

Arafet

González

Moliner

2020

Chemistry A European J

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“…A large number of FP2 inhibitors have been identified (e.g., [15–19]) the majority of which are peptide based, although a number of peptidomimetic (e.g., [20]) and non-peptidic inhibitors (e.g., [21, 22]) have also been found. Despite this proliferation of potential therapeutics, no anti-malarials specifically targeting FP2 are currently available.…”

Section: Introductionmentioning

confidence: 99%

The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site

Machin

Kantsadi

Vakonakis

2019

Malar J

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BackgroundMalaria kills over 400,000 people each year and nearly half the world’s population live in at-risk areas. Progress against malaria has recently stalled, highlighting the need for developing novel therapeutics. The parasite haemoglobin degradation pathway, active in the blood stage of the disease where malaria symptoms and lethality manifest, is a well-established drug target. A key enzyme in this pathway is the papain-type protease falcipain-2.MethodsThe crystallographic structure of falcipain-2 at 3.45 Å resolution was resolved in complex with an (E)-chalcone small-molecule inhibitor. The falcipain-2–(E)-chalcone complex was analysed with reference to previous falcipain complexes and their similarity to human cathepsin proteases.ResultsThe (E)-chalcone inhibitor binds falcipain-2 to the rear of the substrate-binding cleft. This is the first structure of a falcipain protease where the rear of the substrate cleft is bound by a small molecule. In this manner, the (E)-chalcone inhibitor mimics interactions observed in protein-based falcipain inhibitors, which can achieve high interaction specificity.ConclusionsThis work informs the search for novel anti-malaria therapeutics that target falcipain-2 by showing the binding site and interactions of the medically privileged (E)-chalcone molecule. Furthermore, this study highlights the possibility of chemically combining the (E)-chalcone molecule with an existing active-site inhibitor of falcipain, which may yield a potent and selective compound for blocking haemoglobin degradation by the malaria parasite.

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“…The investigators also investigated their selectivity against human CATHs B and L1. Their results showed that they were potent irreversible CPIs, and in vivo antiprotozoal studies showed promising results for treatment of malignant malaria, African sleeping sickness and Chagas' disease, with IC50 values in the micromolar range [29] .…”

Section: Cysteine Proteinase Inhibitors (Cpis)mentioning

confidence: 99%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Abaza

2019

Parasitologists United Journal

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Cysteine proteinases (CPs) Being essential for parasite survival, CPs are investigated for development of vaccine candidates and/or novel drugs in protozoal diseases with high mortality and morbidity rates such as malignant malaria, African sleeping sickness and Chagas' disease, as well as neglected tropical diseases such as visceral leishmaniasis, toxoplasmosis, extraintestinal amoebiasis and cryptosporidiosis. Caffrey and Steverding [1] , in their review, introduced a unified nomenclature for kinetoplastid cathepsins (CATHs) and discussed their expressions in different developmental stages, essential functions, as well as genomic organization. They also discussed the feasibility of application of these CPs in development of vaccine candidates. Recent evolution in molecular technology and bioinformatics enable researchers to localize and analyze the biologic cellular functions of several expressed CPs. In addition, CPs abundance in parasites compared to their mammalian hosts attract scientists to search for specific CP inhibitors for development of safe chemotherapeutic agents without host adverse side effects. In this regard, Caffrey et al., [2] reviewed CPs of clan CA, family C1 in kinetoplastids and discussed their biochemical and genetic diversity as well as their genomics in relation to stage-specificity and expression control. The reviewers aimed at utilizing literature date as first step to achieve development of novel drugs and/or vaccine candidates to control visceral leishmaniasis, African sleeping sickness and Chagas' disease. On the other hand, complete genome sequences of three human pathogenic trypanosomatids, T. brucei, T. cruzi and Leishmania spp. followed by in silico analyses allowed the researchers to identify and assign 23, 40 and 33 genes involved in calpains (CALPs) expression in different stages of T. brucei, T. cruzi and L. braziliensis, respectively. In a review article published two years later, the reviewers discussed the biochemical and biological aspects of CALPs expressed in these trypanosomatids. They focused on the fact that knowing the genome sequences in drug-resistant and-sensitive strains will allow the investigators to investigate the inhibitory efficiency of several CALP inhibitors [3]. Furthermore, CPs were utilized as diagnostic markers. In 2005, Brazilian investigators described SDS-PAGE for in situ detection of CP activity using its specific CP inhibitor to differentiate between flagellates isolated from insects and plants [4]. In the same year, a group of scientists from UK employed genomic analysis to identify genes encoding CALPs in three human kinetoplastids; L. major, T. cruzi, and T. brucei.

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Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates

Cited by 33 publications

References 25 publications

Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes

Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes

The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

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