Structure-based optimization of non-peptidic Cathepsin D inhibitors

Grädler, Ulrich; Czodrowski, Paul; Tsaklakidis, Christos; Klein, Markus; Werkmann, Daniela; Lindemann, Sven; Maskos, K.; Leuthner, Birgitta

doi:10.1016/j.bmcl.2014.07.054

Cited by 18 publications

(9 citation statements)

References 33 publications

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“…Compound 14 with β-naphthyl exhibited the lowest IC 50 of 0.6 nM. Inhibitors with a single aromatic ring (15,16,17, and 9) had slightly higher IC 50 values. The minimal difference between 9 with benzyl and 18 with cyclohexyl-methyl suggested that hydrophobic interaction prevails over aromatic stacking with the several aromatic residues in the S1 pocket.…”

Section: ■ Resultsmentioning

confidence: 98%

“…1 (3S,7S,8S)-8-Benzyl-7-hydroxy-3-isopropyl-1,4,9-triazacyclotetracosane-2,5,10-trione (13). 13 (3S,7S,8S)-8-(3,4-Dichlorobenzyl)-7-hydroxy-3-isopropyl-1,4,9triazacyclohenicosane-2,5,10-trione (16). 1 H NMR (400 MHz, DMSO-d 6 ): 0.83 (6H, d, J = 6.8), 0.84−1.49 (18H, m), 1.95−2.06 (1H, m), 2.08−2.20 (2H, m), 2.20 (1H, dd, J = 14.0, 5.5), 2.33 (1H, dd, J = 14.0, 8.6), 2.61−2.68 (1H, m), 2.69−2.79 (2H, m), 3.25−3.34 (1H, m), 3.79 (1H, dddd, J = 9.7, 9.7, 4.6, 1.2), 3.92 (1H, dd, J = 7.8, 5.8), 3.99−4.04 (1H, m), 5.12 (1H, br s), 7.20 (1H, dd, J = 8.3, 1.9), 7.46 (1H, d, J = 8.3), 7.47 (1H, d, J = 1.9), 7.61 (1H, d, J = 7.9), 7.72 (1H, d, J = 9.4), 7.98 (1H, dd, J = 7.1, 4.5).…”

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

“…Various aspartic proteases are targets for drugs that regulate their proteolytic activity. Renin inhibitors are used to treat hypertension and HIV protease inhibitors to treat HIV infection, whereas β-secretase (BACE1) and plasmepsins are being investigated as targets for drugs against Alzheimer’s disease and malaria, respectively. − Several types of potential small-molecule CatD inhibitors have been designed de novo. − The most potent natural inhibitor of CatD discovered to date is pepstatin A . This linear pseudo-pentapeptide originally isolated from actinobacteria is effective against many aspartic proteases from the pepsin family with inhibition constants as low as 10 –10 M. Its potency is attributable to the nonproteinogenic amino acid statine [(3 S ,4 S )-4-amino-3-hydroxy-6-methylheptanoic acid], the hydroxyl group of which interacts with catalytic aspartate residues and acts as a transition-state analogue.…”

Section: Introductionmentioning

confidence: 99%

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Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

et al. 2020

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Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.

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Section: ■ Resultsmentioning

confidence: 98%

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

et al. 2020

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“…To construct the homology model, the PSI-BLAST [19] was conducted against PDB entries (updated November, 2018) [20]. Two experimentally resolved structures of CatDs derived from the tick Ixodes ricinus (PDB ID: 5N7N, [21]) and humans (PDB ID:4OD9, [22]) were used as templates. The homology model was built on each template and refined using high-resolution energy minimization of YASARA force field [23].…”

Section: Homology Modeling For Structure Analysis Of Cscatd2mentioning

confidence: 99%

Partial Characterization of Two Cathepsin D Family Aspartic Peptidases of Clonorchis sinensis

Kang

Yoo

Lê³

et al. 2019

Korean J Parasitol

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Cathepsin D (CatD, EC 3.4.23.5) is a member belonging to the subfamily of aspartic endopeptidases, which are classified into the MEROPS clan AA, family A1. Helminth parasites express a large set of different peptidases that play pivotal roles in parasite biology and pathophysiology. However, CatD is less well known than the other classes of peptidases in terms of biochemical properties and biological functions. In this study, we identified 2 novel CatDs (CsCatD1 and CsCatD2) of Clonorchis sinensis and partially characterized their properties. Both CsCatDs represent typical enzymes sharing amino acid residues and motifs that are tightly conserved in the CatD superfamily of proteins. Both CsCatDs showed similar patterns of expression in different developmental stages of C. sinensis, but CsCatD2 was also expressed in metacercariae. CsCatD2 was mainly expressed in the intestines and eggs of C. sinensis. Sera obtained from rats experimentally infected with C. sinensis reacted with recombinant CsCatD2 beginning 2 weeks after infection and the antibody titers were gradually increased by maturation of the parasite. Structural analysis of CsCatD2 revealed a bilobed enzyme structure consisting of 2 antiparallel β-sheet domains packed against each other forming a homodimeric structure. These results suggested a plausible biological role of CsCatD2 in the nutrition and reproduction of parasite and its potential utility as a serodiagnostic antigen in clonorchiasis.

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“…Aspartates D97 and D295 as part the catalytic site are highlighted in red. (B) Crystal structure model of mature CTSD consisting of the light chain (blue) and the heavy chain (gray) [PDB-ID: 4OBZ (Gradler et al, 2014 )]. The active site, consisting of the two aspartates D97 and D295, is shown in red.…”

mentioning

confidence: 99%

Corrigendum: Cathepsin D Variants Associated With Neurodegenerative Diseases Show Dysregulated Functionality and Modified α-Synuclein Degradation Properties

Bunk

Huarcaya

Drobny

et al. 2021

Front. Cell Dev. Biol.

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Structure-based optimization of non-peptidic Cathepsin D inhibitors

Cited by 18 publications

References 33 publications

Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

Partial Characterization of Two Cathepsin D Family Aspartic Peptidases of Clonorchis sinensis

Corrigendum: Cathepsin D Variants Associated With Neurodegenerative Diseases Show Dysregulated Functionality and Modified α-Synuclein Degradation Properties

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