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Relevant bibliographies by topics / Aminopeptidases Design

Academic literature on the topic 'Aminopeptidases Design'

Author: Grafiati

Published: 10 December 2022

Last updated: 29 January 2023

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Journal articles on the topic "Aminopeptidases Design"

1

Malcolm, Tess R., Karolina W. Swiderska, Brooke K. Hayes, Chaille T. Webb, Marcin Drag, Nyssa Drinkwater, and Sheena McGowan. "Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases." Biochemical Journal 478, no. 13 (July 16, 2021): 2697–713. http://dx.doi.org/10.1042/bcj20210172.

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During malarial infection, Plasmodium parasites digest human hemoglobin to obtain free amino acids for protein production and maintenance of osmotic pressure. The Plasmodium M1 and M17 aminopeptidases are both postulated to have an essential role in the terminal stages of the hemoglobin digestion process and are validated drug targets for the design of new dual-target anti-malarial compounds. In this study, we profiled the substrate specificity fingerprints and kinetic behaviors of M1 and M17 aminopeptidases from Plasmodium falciparum and Plasmodium vivax, and the mouse model species, Plasmodium berghei. We found that although the Plasmodium M1 aminopeptidases share a largely similar, broad specificity at the P1 position, the P. falciparum M1 displays the greatest diversity in specificity and P. berghei M1 showing a preference for charged P1 residues. In contrast, the Plasmodium M17 aminopeptidases share a highly conserved preference for hydrophobic residues at the P1 position. The aminopeptidases also demonstrated intra-peptide sequence specificity, particularly the M1 aminopeptidases, which showed a definitive preference for peptides with fewer negatively charged intrapeptide residues. Overall, the P. vivax and P. berghei enzymes had a faster substrate turnover rate than the P. falciparum enzymes, which we postulate is due to subtle differences in structural dynamicity. Together, these results build a kinetic profile that allows us to better understand the catalytic nuances of the M1 and M17 aminopeptidases from different Plasmodium species.

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2

Mahon, Cathal S., Anthony J. O'Donoghue, David H. Goetz, Patrick G. Murray, Charles S. Craik, and Maria G. Tuohy. "Characterization of a multimeric, eukaryotic prolyl aminopeptidase: an inducible and highly specific intracellular peptidase from the non-pathogenic fungus Talaromyces emersonii." Microbiology 155, no. 11 (November 1, 2009): 3673–82. http://dx.doi.org/10.1099/mic.0.030940-0.

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Fungi are capable of degrading proteins in their environment by secreting peptidases. However, the link between extracellular digestion and intracellular proteolysis has scarcely been investigated. Mycelial lysates of the filamentous fungus Talaromyces emersonii were screened for intracellular peptidase production. Five distinct proteolytic activities with specificity for the p-nitroanilide (pNA) peptides Suc-AAPF-pNA, Suc-AAA-pNA, K-pNA, F-pNA and P-pNA were identified. The native enzyme responsible for the removal of N-terminal proline residues was purified to homogeneity by ammonium sulfate fractionation followed by five successive chromatographic steps. The enzyme, termed Talaromyces emersonii prolyl aminopeptidase (TePAP), displayed a 50-fold specificity for cleaving N-terminal Pro–X (k cat/K m=2.1×106 M−1 s−1) compared with Ala–X or Val–X bonds. This intracellular aminopeptidase was optimally active at pH 7.4 and 50 °C. Peptide sequencing facilitated the design of degenerate oligonucleotides from homologous sequences encoding putative fungal proline aminopeptidases, enabling subsequent cloning of the gene. TePAP was shown to be relatively uninhibited by classical serine peptidase inhibitors and to be sensitive to selected cysteine- and histidine-modifying reagents, yet gene sequence analysis identified the protein as a serine peptidase with an α/β hydrolase fold. Northern analysis indicated that Tepap mRNA levels were regulated by the composition of the growth medium. Highest Tepap transcript levels were observed when the fungus was grown in medium containing glucose and the protein hydrolysate casitone. Interestingly, both the induction profile and substrate preference of this enzyme suggest potential co-operativity between extracellular and intracellular proteolysis in this organism. Gel filtration chromatography suggested that the enzyme exists as a 270 kDa homo-hexamer, whereas most bacterial prolyl aminopeptidases (PAPs) are monomers. Phylogenetic analysis of known PAPs revealed two diverse subfamilies that are distinguishable on the basis of primary and secondary structure and appear to correlate with the subunit composition of the native enzymes. Sequence comparisons revealed that PAPs with key conserved topological features are widespread in bacterial and fungal kingdoms, and this study identified many putative PAP candidates within sequenced genomes. This work represents, to our knowledge, the first detailed biochemical and molecular analysis of an inducible PAP from a eukaryote and the first intracellular peptidase isolated from the thermophilic fungus T. emersonii.

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3

Tsoukalidou, Sofia, Magdalini Kakou, Ioannis Mavridis, Despoina Koumantou, Vito Calderone, Marco Fragai, Efstratios Stratikos, Athanasios Papakyriakou, and Dionisios Vourloumis. "Exploration of zinc-binding groups for the design of inhibitors for the oxytocinase subfamily of M1 aminopeptidases." Bioorganic & Medicinal Chemistry 27, no. 24 (December 2019): 115177. http://dx.doi.org/10.1016/j.bmc.2019.115177.

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4

Gordon, E. M., J. D. Godfrey, N. G. Delaney, M. M. Asaad, D. Von Langen, and D. W. Cushman. "Design of novel inhibitors of aminopeptidases. Synthesis of peptide-derived diamino thiols and sulfur replacement analogs of bestatin." Journal of Medicinal Chemistry 31, no. 11 (November 1988): 2199–211. http://dx.doi.org/10.1021/jm00119a023.

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5

Tholander, Fredrik, Ayumo Muroya, Bernard-Pierre Roques, Marie-Claude Fournié-Zaluski, Marjolein M. G. M. Thunnissen, and Jesper Z. Haeggström. "Structure-Based Dissection of the Active Site Chemistry of Leukotriene A4 Hydrolase: Implications for M1 Aminopeptidases and Inhibitor Design." Chemistry & Biology 15, no. 9 (September 2008): 920–29. http://dx.doi.org/10.1016/j.chembiol.2008.07.018.

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6

Wanat, Weronika, Michał Talma, Błażej Dziuk, and Paweł Kafarski. "Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases." Biomolecules 10, no. 9 (September 14, 2020): 1319. http://dx.doi.org/10.3390/biom10091319.

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A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

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7

Irfan, Iram, Asghar Ali, Bharati Reddi, Mohd Abrar Khan, Phool Hasan, Sarfraz Ahmed, Amad Uddin, et al. "Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors." Antibiotics 11, no. 8 (August 19, 2022): 1126. http://dx.doi.org/10.3390/antibiotics11081126.

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Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones (PS1–14) to identify potent and selective bacterial MetAPs inhibitors. Compound PS9 inhibited prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a and SpMetAP1a with Ki values of 0.31, 6.93 and 0.37 µM, respectively. Interestingly, PS9 inhibited the human analogue HsMetAP1b with Ki (631.7 µM) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, PS6 and PS9 had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. PS9 showed no significant cytotoxic effect on human RBCs, HEK293 cells and Galleria mellonella larvae in vivo. PS9 inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested PS9 could be a useful candidate for the development of antibacterial alternatives.

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8

Reid, A., A. Protheroe, G. Attard, C. Cowsill, J. Spicer, L. Vidal, E. Bone, L. Hooftman, A. Harris, and J. S. De-Bono. "A phase 1 dose finding study of CHR-2797, an inhibitor of M1 aminopeptidases, in patients with advanced solid tumours." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3053. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3053.

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3053 Background: CHR-2797 is a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases, in particular PuSA, and LTA4 hydrolase. Exposure of cancer cells to CHR-2797 results in the generation of the active metabolite CHR-79888 which is poorly membrane-permeable, resulting in intracellular accumulation. CHR-2797 has shown anti-proliferative activity in syngeneic (rat) and xenograft (mouse) cancer models, and is anti-angiogenic in vitro. Methods: Patients (pts) (ECOG PS ≤ 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. The accelerated titration design of the trial involved two phases for evaluation of schedule and dose: 1) fixed dose with increasing duration, and 2) dose escalation over a fixed duration (28 days). Results: 16 pts (median age: 64.5 years [range 48.8–80.1], 13M/3F)were treated with once daily doses ranging from 10mg to 130mg. The first four patients received a 10mg dose for 7, 14, 21 or 28 days respectively. Five subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity ≥ Grade 2. Thereafter dose was escalated in ≤ 40% increments in 3-patient cohorts. The most frequent adverse events were: gr 1–2 thrombocytopenia (44%), gr 1 diarrhea (25%), gr 1–2 transaminitis (19%), gr 1–2 fatigue (13%), gr 1 hot flushes (13%), and gr 1 lightheadedness (13%). There were no DLTs. Five patients continued therapy after 28 days; stable disease has been achieved in 1 pt for 6 months with granulosa cell carcinoma of ovary, who was progressing prior to study entry. CHR-2797 and CHR-79888 demonstrate dose proportional increases in AUC and Cmax. The terminal half-life for CHR-2797 is around 1–2 hours, whereas it is between 9 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to both CHR-2797 and CHR-79888 is good, with CHR-79888 accumulating over 28 days, such that by day 28 the intracellular levels are comparable to plasma. Conclusions: CHR-2797 is well tolerated and can be safely administered at doses that reach plasma concentrations associated with activity in pre-clinical models. Accrual into the study continues. No significant financial relationships to disclose.

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Protheroe, A., A. Reid, G. Attard, A. Davies, J. Spicer, L. Vidal, E. Bone, L. Hooftman, A. Harris, and J. De-Bono. "First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3537. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3537.

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3537 Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (> 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK. No significant financial relationships to disclose.

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10

Grembecka, J., and P. Kafarski. "Leucine Aminopeptidase as a Target for Inhibitor Design." Mini-Reviews in Medicinal Chemistry 1, no. 2 (July 1, 2001): 133–44. http://dx.doi.org/10.2174/1389557013406990.

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Dissertations / Theses on the topic "Aminopeptidases Design"

1

Andersson, Hanna. "Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-122218.

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Book chapters on the topic "Aminopeptidases Design"

1

Salazar, Cecilia, José F. Tort, and Carlos Carmona. "Design of a Peptide-Carrier Vaccine Based on the Highly Immunogenic Fasciola hepatica Leucine Aminopeptidase." In Methods in Molecular Biology, 191–204. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0475-5_14.

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