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Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
In 1973 Camargo et al. reported on the presence of a bradykinin-hydrolyzing endopeptidase in the supernatant fraction of a rabbit brain homogenate87. The enzyme cleaved bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) at the Phe5-Ser6 bond. It was partially purified by chromatography on Sephadex G-100® and DEAE columns. This enzyme displayed a pH optimum in the neutral range, was inhibited by the thiol blocking agent p-chloromercuribenzoate, and was stimulated by the thiol reducing agent dithiothreitol. It was unable to hydrolyze denatured hemoglobin. Subsequent studies established a molecular weight of 71,000, an isoelectric point of 5.2, and an inability of the enzyme to hydrolyze the denatured bradykinin precursor kininogen46. The enzyme was named endo-oligopeptidase A since it was also unable to hydrolyze Gly-Gly-Gly-Arg-bradykinin when this peptide was coupled to either Affi-Gel 10 or to succinylated polylysine49. In 1983 Orlowski et al. described a cytosolic metalloendopeptidase purified from rat brain by a procedure similar to that used for endo-oligopeptidase A. This enzyme also cleaved bradykinin at the Phe5-Ser6 bond88. The Enzyme Nomenclature Committee recognizes the soluble metalloendopeptidase and endo-oligopeptidase A as the same enzyme and has renamed it “thimet oligopeptidase”15. However Camargo and co-workers maintain that the two enzymes are distinct molecules. The properties of thimet oligopeptidase are reviewed below as is the evidence concerning the identity of the two enzymatic activities.
Gene Delivery
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
The same is true for polypeptides (polylysine, polyarginine, and polyhistidine). Polypeptides are in general toxic and several authors report that polylysine is toxic. Poly(l-lysine) is, in contrast to poly(d-lysine) and polybrene, biodegradable and is less toxic. Many new and shorter polypeptides are being synthesized and studied but the information on their in vivo activity and toxicity has not been reported yet.
Melanotropic Peptides: Biomedical Applications
Published in Mac E. Hadley, The Melanotropic Peptides, 2018
Dhirendra N. Chaturvedi, Mac E. Hadley
Macromolecular polypeptides such as polylysin and polyglutamic acid have been used as carriers in their own right as well as functioning to alter the structure or charge of other carrier complexes. Polylysine possesses exceptional cell-membrane-penetrating properties. It is of interest to note that the methotrexate transport deficiency in tumor cells has been overcome in many experiments by the use of the polylysine carrier system.108,109 Some measure of differential selectivity could be introduced to these molecules if they are conjugated to our unique melanotropins. The melanotropin-bound drug can ensure that elevated levels of the drug are held compartmentalized within a body cavity and thus provide a continuously higher level of drug delivery. The polymer-bound drug can also overcome transport blocks which certain cells possess and prevent passage of the free drug into the cell.
Pharmacokinetics of oral therapeutics delivered by dendrimer-based carriers
Published in Expert Opinion on Drug Delivery, 2019
Venkata K. Yellepeddi, Hamidreza Ghandehari
The absorption and biodistribution of fourth-generation lipidic peptide(lysine) dendrimers in rats were reported by Florence et al. [68]. The results have shown that the maximum uptake of dendrimers was observed 6 h after oral administration and after 24 h negligible amounts of dendrimer was recovered [68]. Furthermore, the study reported that Peyer’s patches played a small role in the uptake of polylysine dendrimers when compared to enterocytes at 12 h. The study shows that polylysine dendrimers have longer circulation times after oral administration when compared to PAMAM dendrimers (Only 0.25% remaining after 4 h). However, the study did not report any toxicity information, and the in vivo absorption study is performed as a single (14 mg/kg) dose of polylysine dendrimers.
Novel microencapsulated probiotic blend for use in metabolic syndrome: design and in-vivo analysis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Umar Haris Iqbal, Susan Westfall, Satya Prakash
In addition to the risk factors of the metabolic syndrome, this syndrome has also been associated with a proinflammatory state [51]. The present study investigated the anti-inflammatory properties of the microencapsulated probiotic blend by quantifying serum CRP levels. The administration of APA microcapsules was observed to cause no significant shift in serum CRP levels, however, when compared to the CRP levels of the high-fat control group, it was observed that the latter stayed almost constant throughout the treatment and washout period, whereas the microcapsule group did not. The hamsters that received microcapsules showed to have an increase in CRP levels by the end of the treatment period (however not significant), and then a reduction in CRP levels after the treatment ended. These results were surprising as both L. fermentum NCIMB 5221 and L. plantarum NCIMB 8826, which are present in the blend, have been found to have anti-inflammatory properties [26,50]. These findings postulate that APA microcapsules could be causing an inflammatory response, but due to the findings not being significant, no concrete conclusion can be made. It has been suggested that polylysine could induce an inflammatory response [52]. However, the same study also found that combining polylysine with alginate, and maintaining a low content of polylysine, as done in the present study, would reduce the inflammatory response [52]. Further investigation would need to be done to have a better understanding as to why this was observed.
Polyaminoacid-based nanocarriers: a review of the latest candidates for oral drug delivery
Published in Expert Opinion on Drug Delivery, 2020
Sandra Robla, Maria José Alonso, Noemi S. Csaba
Polylysine (PLL, Figure 2(d)) has been of the first polyaminoacids commonly used in drug and gene delivery due to its ability of interacting with membranes [66]. More recently, it has also been investigated for the oral delivery of peptides and proteins. For instance, the design of lipidic peptide PLL dendrimers with long alkyl chains was reported to be useful for the oral delivery of hydrophobic drugs. A maximum peak of 15% of the initially administered dose of dendrimers was observed in small intestine after 6 h oral administration [67]. An advanced PLL system was designed to enhance the immunogenicity of a peptide antigen administered orally. The link of a lipoamino acid together with polylysine formed a hybrid micelle structure that can be used in vaccine or therapeutic drug [68]. In another example, the combination of the oppositely charged cationic peptide polylysine and anionic polyglutamic acid formed colloidal polyelectrolyte complexes which could be used for the oral delivery of bioactive agents, vitamins, or nutraceuticals [69]. Modified PLL with tocopheryl (TP) and succinyl (SC) branches originated polymeric lipid vesicles (PLVs). Their core-shell structure provides protection to insulin from enzymatic degradation and pH-dependent controlled release [70]. Upon oral gavage, insulin-loaded PLVs reduced blood glucose levels to 72% (at 4 h) and 63% (at 6 h) post administration [71]. A different prototype based on insulin-containing PLL nanoparticles was also reported to protect insulin from degradation and facilitate its transport across the Caco-2 monolayer. The hypoglycemic effect induced by these nanoparticles was dependent on the PLL coating density, showing higher efficiency with dense surface coating (50% decrease in plasma glucose levels) than with low PLL density (30% decrease) upon intraintestinal administration to diabetic rats [72].