Role of Lipids in Spheroidal High Density Lipoproteins

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly

Synthesis and biological activity of analogues of leucine-/methionine-enkephalin

Seven analogues of opioid pentapeptides leucine-/methionine-enkephalinamides have been synthesised by the solid phase technique employing mainly 9-fluorenylmethyloxycarbonyl amino acid active esters in presence of 1-hydroxybenzotriazole and the conventional chloromethylated copolystyrene-2% divinylbenzene (Merrifield) resin as the solid support. The analogues were obtained by replacing the amino acids at positions 2 and 5. Some of the analogues were found, to be highly potent in the guinea pig ileum assay

Synthesis and pharmacological properties of oxytocin analogues having penicillamine

Six analogs of oxytocin having penicillamine (L or D) at position 1,​p-​hydroxyphenylglycine (Hpg, L or D) at position-​2 and​/or threonine (L or D) at position-​4 have been synthesized by the solid-​phase method and tested for oxytocic, antioxytocic and antidiuretic activities. All the six analogs antagonize the action of oxytocin on rat uterus in the presence of Mg2+ in vitro. One of the analogs, [L-​Pen1,​L-​Hpg2]​-​oxytocin, is a dose-​dependent potent inhibitor of oxytocic activity. They also exhibit low antidiuretic activity

Synthesis and pharmacological properties of oxytocin analogs having penicillamine

Six analogs of oxytocin having penicillamine (L or D) at position 1,​p-​hydroxyphenylglycine (Hpg, L or D) at position-​2 and​/or threonine (L or D) at position-​4 have been synthesized by the solid-​phase method and tested for oxytocic, antioxytocic and antidiuretic activities. All the six analogs antagonize the action of oxytocin on rat uterus in the presence of Mg2+ in vitro. One of the analogs, [L-​Pen1,​L-​Hpg2]​-​oxytocin, is a dose-​dependent potent inhibitor of oxytocic activity. They also exhibit low antidiuretic activity

Anti-inflammatory peptides grab on to the whiskers of atherogenic oxidized lipids

AbstractThe peptide 4F is known to have potent anti-atherogenic activity. 4F is an 18 residue peptide that has a sequence capable of forming a class A amphipathic helix. Several other class A amphipathic helical, 18 residue peptides with the same polar face but with increasing Phe residues on the nonpolar face have been synthesized with varying degrees of biological activity. In this work we compared the properties of the original 2F peptide, modeled on the consensus sequence of the amphipathic helical segments of the apolipoprotein A-I with the peptide 4F that has two Leu residues replaced with Phe. We demonstrate that the more biologically active 4F peptide has the greatest affinity for binding to several molecular species of oxidized lipids. Lipoprotein particles can be formed by solubilizing 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) with peptides. These solubilized lipoprotein particles extract oxidized lipid from liposomes of POPC containing 5 mol% of oxidized lipid. The peptides with the strongest anti-atherogenic activity interact most strongly with the oxidized lipid. The results show that there is a correlation between the biological potency of these peptides and their ability to interact with certain specific cytotoxic lipids, suggesting that this interaction may contribute favourably to their biological properties

Regulation of pattern recognition receptors by the apolipoprotein A-I mimetic peptide 4F

The apolipoprotein A-I (apoA-I) mimetic peptide 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype and attenuates lipopolysaccharide (LPS)-induced inflammatory responses. We investigated the effects of LPS on the Toll-like receptor (TLR) signaling pathway in 4F-differentiated monocyte-derived macrophages

Bovine HDL and Dual Domain HDL-Mimetic Peptides Inhibit Tumor Development in Mice.

A growing body of literature supports the role of apolipoproteins present in HDL in the treatment of pro-inflammatory diseases including cancer. We examined whether bovine HDL (bHDL) and three dual-domain peptides, namely AEM-28 and its analog AEM-28-2, and HM-10/10, affect tumor growth and development in mouse models of ovarian and colon cancer. We demonstrate that bHDL inhibits mouse colorectal cancer cell line CT26-mediated lung tumor development, and mouse ovarian cancer cell line ID8-mediated tumor burden. We also demonstrate that, although to different degrees, dual-domain peptides inhibit cell viability of mouse and human ovarian and colon cancer cell lines, but not that of normal human colonic epithelial cells or NIH3T3 mouse fibroblasts. Dual-domain peptides administered subcutaneously or in a chow diet decrease CT26 cell-mediated tumor burden, tumor growth, and tumor dissemination in BALB/c mice. Plasma levels of lysophosphatidic acid (LPA) are significantly reduced in mice that received bHDL and the dual-domain peptides, suggesting that reduction by effecting accumulation and/or synthesis of pro-inflammatory lipids may be one of the mechanisms for the inhibition of tumor development by bHDL and the dual-domain peptides. Our studies suggest that therapeutics based on apolipoproteins present in HDL may be novel agents for the treatment of epithelial adenocarcinomas of the ovary and colon

Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly.

Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol