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The Renin-Angiotensin System
Published in Austin E. Doyle, Frederick A. O. Mendelsohn, Trefor O. Morgan, Pharmacological and Therapeutic Aspects of Hypertension, 2020
This N-acylated pentapeptide (Figure 78) was discovered in, and isolated from, cultures of the microbe Actinomycetes.590 It has been synthesized and shown to be an inhibitor of several acid proteases,591 including pepsin, gastric rennin,592 and cathepsin D.593 Inhibition of renin by pepstatin has been reported both in vitro and in vivo.43,44 Kinetic studies with hog renin and rat-plasma angiotensinogen showed pepstatin to be a reversible inhibitor.594 Detailed kinetic studies using human renin and a synthetic polymeric peptide substrate also showed pepstatin to be a very potent, reversible, noncompetitive inhibitor in this system596 (Figure 79). However, pepstatin was reported to be a competitive inhibitor of rabbit renin acting on rabbit plasma substrate.595
Plant Species from the Atlantic Forest Biome and Their Bioactive Constituents
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Rebeca Previate Medina, Carolina Rabal Biasetto, Lidiane Gaspareto Felippe, Lilian Cherubin Correia, Marília Valli, Afif Felix Monteiro, Alberto José Cavalheiro, Ângela Regina Araújo, Ian Castro-Gamboa, Maysa Furlan, Vanderlan da Silva Bolzani, Dulce Helena Siqueira Silva
Jatropha species have shown a great potential as source of small cyclic peptides, which have attracted much attention due to their chemo-diversity and variety of important biological activities (Baraguey et al., 2001; Mongkolvisut et al., 2006). Chemical studies on the latex of Jatropha curcas led to isolation, structural elucidation and conformational studies of the cyclic peptide jatrophidin I (122) (Figure 9.27). The compound's biological evaluation showed strong inhibitory activity in a fluorometric protease inhibition assay using pepsin as a molecular model for aspartic protease inhibition (Gold et al., 2007), with IC50 value of 0.88 µM, when compared to standard pepstatin A (IC50 0.40 µM). However, the cyclic peptide did not inhibit the serine protease subtilisin, evidencing that the observed inhibitory activity was specific for aspartic proteases (Altei et al., 2014).
Structural determinants for subnanomolar inhibition of the secreted aspartic protease Sapp1p from Candida parapsilosis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Jiří Dostál, Jiří Brynda, Lucie Vaňková, Syeda Rehana Zia, Iva Pichová, Olga Heidingsfeld, Martin Lepšík
Admittedly, it is beyond the capabilities of the used approach to pinpoint the fine structural determinants of potency between pepstatin A and the pepstatin-based inhibitors. One reason is the disorder in the crystal structures, which has prevented unequivocal localisation of the C-terminal parts of the pepstatin-based inhibitors as well as water molecules at the protein-inhibitor interface that may stabilise the complexes. Another factor is the dynamics of the inhibitor and the surrounding protein amino acids, which may also influence the binding affinities. Last but not least, quantum effects such as proton transfer may occur between the active-site aspartates40. Various computational approaches could be used to address these phenomena. Molecular dynamics (MD) can provide insights into the flexibility of the complexes and solvation patterns41,42. MD-based energy analyses, such as the popular MM-GB/PBSA, are useful for obtaining interaction energies and their components and residue contributions43–45. Quantum mechanics (QM) is a method of choice for cases where quantum effects play a role in protein–ligand binding31,46,47.
Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Marcela Q. Granato, Ingrid S. Sousa, Thabatta L. S. A. Rosa, Diego S. Gonçalves, Sergio H. Seabra, Daniela S. Alviano, Maria C. V. Pessolani, André L. S. Santos, Lucimar F. Kneipp
Peptidase activity was determined using 7-methoxycoumarin-4-acetyl (MCA)-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-amide (cathepsin D fluorogenic substrate, Sigma-Aldrich Chemical Co) as described by Santos et al.29. The assay was performed in triplicate using a 96-well microtiter plate. Briefly, the reaction was started by the addition of substrate (12 µM) to fungal concentrated supernatant (1 µg of protein) in a buffer containing 100 mM sodium acetate, pH 4.7, 1 M sodium chloride, 1 mM ethylenediamine tetraacetic acid (EDTA), 1 mM dithiothreitol (DTT), 10% DMSO and 1 mg/mL bovine serum albumin (BSA). The system was treated with pepstatin A (10 µM) or 100 µM of HIV-PIs (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir) and a non-treated system was used as control. After 30 min, the cleavage of the cathepsin D substrate was detected in a spectrofluorimeter (FlexStation 3, Molecular Devices, CA, USA) with 328 nm excitation and 393 nm emission wavelengths. The proteolytic activity was calculated based on a standard curve of MCA fluorophore. Protein concentration was measured using the method described by Lowry et al.28. All HIV-PIs were purchased from National Institutes of Health (NIH, MA, USA) and dissolved in DMSO. All buffer reagents were obtained from Sigma-Aldrich Chemical Co (St Louis, MO, USA).