Lipophilic peptide

Lipophilic peptide Multi-Nucleoside reverse transcriptase inhibitor conjugates synthesis to combat HIV resistance... 

S. Muranishi, A. Sakai, K. Yamada, M. Murakami, K. Tanaka, Y. Kiso, Lipophilic Peptides Synthesis of Lauryol Thyrotropin-Releasing Hormone and Its Biological Activity ,... 

Yang, Q., Benson, L. M., Johnson, K. L., and Naylor, S. (1999). Analysis of lipophilic peptides and therapeutic drugs-on-line- nonaqueous capillary-electrophoresis mass-spectrometry. /. Biochem. Biophys. Methods 38, 103 — 121. 

Since its introduction into clinical use in about 1979 the immunosuppresant cyclosporin has been responsible for a revolution in human organ transplantation.3 The exact mechanism of action in suppressing T-lymphocyte-mediated autoimmune responses is still not completely clear, but cyclosporin, a cyclic lipophilic peptide from a fungus, was found to bind to specific proteins that were named cydophilins.d Human cyclophilin A is a 165-residue protein which associates, in the crystal form, as a decamer with five-fold rotational and dihedral symmetry.6 This protein is also found in almost all... 

Put into a microfuge tube 50 pL formamide (for lipophilic peptides add instead 25 pL formamide and 25 pL acetonitrile). 

Wimmer, N., Marano, R. J., Kearns, P. S., Rakaczy, E. P., and Toth, I. (2002) Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides. Biorg. Med. Chem. Lett. 12, 2635-2631. 

There are a few marketed drug delivery systems containing microemulsions that are related to the lipid systems we describe here. Sandimmune Neoral (Novartis, Switzerland) [17], which delivers the lipophilic peptide cyclosporin A, is based on medium-chain triglycerides obtained from coconut oil, a semisynthetic emulsifier (ricinoleate), and propylene glycol. The absorption of the drug taken orally as a microemulsion increases dramatically compared to that of an aqueous suspension [17]. Another marketed example, in which Cs/Cio triglycerides from coconut oil are used, is a soft gelatin capsule of vitamin D3 [18]. 

Also, the Schreiner group published in 2009 a desymmetrisation approach of meso-(cyclo)alkane-l,2-diols applying the lipophilic peptide catalyst 7 (Scheme 13.8) already successfully used in kinetic resolution processes (Scheme 13.5) as previously described. The desymmetrisation step was combined in one pot with a direct TEMPO oxidation to the corresponding ot-aceto)y ketone in order to avoid racemisation of the monoacelylated intermediate. 

Usually, C18, C8, C4, phenyl and CN phases, or even polystyrenes are used for the RPC of peptides. The bonding used depends on the polarity, size, and higher structure of the peptides or proteins. Polar phases (C8, C4, phenyl, CN) tend to be used for polar compounds, because they have a higher selectivity in the polar range. C18 is usually used for lipophilic compounds, because it has the best solu-bihty thanks to its high amount of ACN that is needed for elution. If the lipophilic peptide or protein sticks to the surface, polar phases are used too. In this case, it must be ensured that, when the amount of water increases, the peptide or protein is still soluble. In the case of bigger peptides or proteins, shorter chains (C4) are advantageous, because then the accessibility to the pores is increased. 

With a hexosomal formulation based on the GMO/OA/ PX407/water system Lopes et al. could demonstrate enhanced skin permeation of the lipophilic peptide cyclosporin A (CycA) as well as for fluorescein isothiocyanate.The effect was mainly... 

MacrotetroHdes of the valinomycin group of electrically neutral antibiotics form stable 1 1 complexes with alkaH metal ions that increase the cation permeabiHty of some biological and artificial lipophilic membranes. This solubiHzation process appears to have implications in membrane transport research (30) (see Antibiotics, peptides). 

Muratovska a., Lightowlers R. N., Taylor R.W., Turnbull D.M., Smith R.A. J., WiLCE J.A., Martin S.W., Murphy M.P. Targeting peptide nucleic acid (PNA) oligomers to mitochondria within cells by conjugation to lipophilic cations implications for mitochondrial DNA replication, expression and disease. Nucleic Acids Res. 2001 29 1852-1863. 

Nanosize particles of polyacrylic acid were synthesized in w/o microemulsions using azobisisobutyronitrile as lipophilic radical initiator, which were considered suitable for encapsulation of peptides and other hydrophilic drugs [195],... 

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

Some of their derivatives have been used as antiviral drugs. Due to their flexible chemistry, they can be exploited to design drug delivery systems and in molecular nanotechnology. In such systems, they can act as a central lipophilic core and different parts like targeting segments, linkers, spacers, or therapeutic agents can be attached to the said central nucleus. Their central core can be functionalized by peptidic and nucleic acid sequences and also by numerous important biomolecules. 

Esterification increases the lipophilic character of the pigments that has been recogiuzed as an important factor for interactions with the peptide chains of proteins. The hydrolysis of this side chain results in chlorophyllides and the concomitant removal of the Mg + ion in pheophorbides. Only a Umited number of natural chlorophylls in plants and photosynthetic organisms has been described and is well... 

Depicted in Fig. 2, microemulsion-based liquid liquid extraction (LLE) of biomolecules consists of the contacting of a biomolecule-containing aqueous solution with a surfactant-containing lipophilic phase. Upon contact, some of the water and biomolecules will transfer to the organic phase, depending on the phase equilibrium position, resulting in a biphasic Winsor II system (w/o-ME phase in equilibrium with an excess aqueous phase). Besides serving as a means to solubilize biomolecules in w/o-MEs, LLE has been frequently used to isolate and separate amino acids, peptides and proteins [4, and references therein]. In addition, LLE has recently been employed to isolate vitamins, antibiotics, and nucleotides [6,19,40,77-79]. Industrially relevant applications of LLE are listed in Table 2 [14,15,20,80-90]. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Using liposomes made from phospholipids as models of membrane barriers, Chakrabarti and Deamer [417] characterized the permeabilities of several amino acids and simple ions. Phosphate, sodium and potassium ions displayed effective permeabilities 0.1-1.0 x 10 12 cm/s. Hydrophilic amino acids permeated membranes with coefficients 5.1-5.7 x 10 12 cm/s. More lipophilic amino acids indicated values of 250 -10 x 10-12 cm/s. The investigators proposed that the extremely low permeability rates observed for the polar molecules must be controlled by bilayer fluctuations and transient defects, rather than normal partitioning behavior and Born energy barriers. More recently, similar magnitude values of permeabilities were measured for a series of enkephalin peptides [418]. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

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