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Neuropeptide Inactivation By Peptidases
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Gerard O’Cuinn, Brendan O’Connor, Laura Gilmartin, Maria Smyth
It should be noted that products of pyroglutamate aminopeptidase II action on TRH are pyroglutamate and His-ProNH2. (See Figure 1.) The latter metabolite has been shown to cyclize spontaneously and non-enzymatically to form His-Pro diketopiperazine190,191,192 a compound which has been shown to have biological activity in the CNS115,191,192. Brain synaptosomal membranes have been shown to contain dipeptidyl aminopeptidase activity108,111 which has been shown to act on a range of peptides containing proline in the penultimate position from the N-terminus including His-Pro NH2, which is converted to His-Pro and NH3108. With its synaptosomal membrane location this dipeptidyl aminopeptidase, which is most probably dipeptidyl aminopeptidase IV, is well placed to compete with the cyclization process and convert His-ProNH2 to His-Pro. Such competition has been demonstrated using synaptosomal membrane preparations in vitro108.
Proteases as Biocatalysts for the Synthesis of Model Peptides
Published in Willi Kullmann, Enzymatic Peptide Synthesis, 1987
Similar findings to those described above concerning the efficiency of α-chymotrypsin-catalyzed syntheses with aromatic Nα-blocked, COOH-terminally free amino acids as acyl-donors were reported by Luisi and co-workers.20,21 During these syntheses which took place at pH 6.520 and 7.721, respectively, dipeptide amides, amino acid methyl- and ethylester were used as amine components. The low yields in tripeptide amides obtained in some of these reactions20 were possibly caused by side reactions of the amine components (in the present case of the dipeptide amides) during the prolonged incubation period of 2 to 5 days. Thus, since the dipeptide amides have an aromatic amino acid residue in the C-terminal position, they may be chymotryptically deaminated and/or transformed via ring closure to the respective diketopiperazines.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Fytas et al. (2011) discovered acetohydroxamic acids as a new class of compounds with potential antitrypanocidal activity. The synthesis of these compounds was realized through the attachment of an acetohydroxamic acid moiety to the imidic nitrogen of 2,6-diketopiperazines. A SAR study revealed that compounds 83 (S-enantiomer), 84 (R-enantiomer) and 85 (racemic mixture of 83 and 84) (Figure 30) showed low nanomolar activity against the bloodstream-form of T. brucei with IC50 values 6.8 ± 1.4, 9.1 ± 0.2 and 17± 1 nM, respectively, while compound 83, along with compounds 86 and 87, displayed significant activity against T. cruzi with IC50 values 0.21 ± 0.04, 5.51 ± 0.68 and 3.62 ± 0.31 μM, respectively. Overall, compound 83 proved to be the most active compound against both species. In addition, these compounds showed very good selectivity indices. The fact that replacement of the hydroxamic acid moiety led to compounds with decreased activity makes this group a requisite for trypanocidal activity. A small library of hydroxamic acid derivatives, which inhibit human histone deacetylases, was synthesized and tested against cultured bloodstream form T. brucei (Kelly et al. 2012). Most of these compounds exhibited very good activity in the submicromolar range. Specifically, the most promising compounds were 88–90 (Figure 31) with IC50 values 0.034 ± 0.002, 0.064 ± 0.005 and 0.086 ± 0.009 μM, respectively. Structures of hydroxamic acids 83–87.Structures of the most active hydroxamic acids 88–90.
Benefit and risk evaluation of quinapril hydrochloride
Published in Expert Opinion on Drug Safety, 2023
Maryam Barkhordarian, Jannel A. Lawrence, Sebahat Ulusan, Muhammed Ibrahim Erbay, Wilbert S. Aronow, Rahul Gupta
Furthermore, the pharmacokinetics of quinapril and quinaprilat were studied in 12 patients with CHF, half of whom had an EF below 35 and the other half with an EF between 35 and 50 [46]. In the study, quinapril was administered at doses of 10 mg twice a day, and patients with heart failure tolerated these doses well [46]. According to the results, the average c-max value of quinapril was 362, while the average t-max value was 1.88 hours [46]. In addition, there was no elimination or dose adjustment in the heart failure drug half-life [46]. Absorption and conversion of quinapril to quinaprilat was rapid and dose-proportional [46]. Still, clearance of quinapril and quinaprilat from the body is not dose-independent, and conversion to its inactive metabolite, diketopiperazine, is uncommon [47].
Alkaloids as the natural anti-influenza virus agents: a systematic review
Published in Toxin Reviews, 2018
Mohammad-Taghi Moradi, Ali Karimi, Zahra Lorigooini
Chen et al. (2015) isolated 27 prenylated diketopiperazine indole alkaloids from from marine-derived fungus Eurotium rubrum and tested them for activity against influenza A/WSN/33 virus. They demonstrated that the neoechinulin B was active against multidrug resistant influenza A clinical isolates. The mode of action suggested for neoechinulin B was binding to influenza envelope hemagglutinin, which disturbed its interaction with the sialic acid receptor and inhibited the attachment of viruses to host cells. Further analysis of the activity and structure indicated that the alkaloids that were isolated may have potential anti-influenza A virus effects. Analogues have exhibited different anti-virus activities depending on the substituent groups and the olefinic location at diketopiperazine unit. The analogs with a saturated C8–C9 bond exerted weak antiviral effects. For the analogs with a Δ8,9 bond, compound 4 with a Δ12,15 unit at the diketopiperazine moiety instead of alanine unit improved the antiviral activity significantly. Compound rubrum line N with a MeO group at C-8 increased antiviral effect compared with rubrum line M in which an OH group was substituted at C-8. Moreover, an isoprenylor oxygenated isoprenyl group at indole ring is considered an unpleasant group to scaffold indole-bearing diketopiperazines for antiviral effects, as it can be seen in compound neoechinulin B which exhibited the highest potency of antiviral effect of all isolated alkaloids (Chen et al., 2015).
Human probiotic bacteria attenuate Pseudomonas aeruginosa biofilm and virulence by quorum-sensing inhibition
Published in Biofouling, 2020
Myriam Anabel Díaz, Silvia Nelina González, María Rosa Alberto, Mario Eduardo Arena
Diketopiperazines are small cyclic dipeptides, commonly found in many natural resources such as fungi, and Gram-positive and Gram-negative bacteria. These pyrrole molecules exhibit multiple biological functions such as antibacterial, antifungal, antiviral, antitumor, and antihyperglycaemic activities (El-Gendy and Rateb 2015; Marrez et al. 2019) and also are recognized as QS inhibitors that influence cell-to-cell communication (Sun et al. 2016). The possible mechanism of anti-QS activity might be the interaction with the QS receptors and further preventing the binding of effector molecules to DNA, therefore, interfering with the transcription of virulence genes (Parasuraman et al. 2020).