title: Tartaric acid-based amphiphilic macromolecules with ether linkages exhibit enhanced repression of oxidized low density lipoprotein uptake.
abstract: Cardiovascular disease initiates with the atherogenic cascade of scavenger receptor- (SR-) mediated oxidized low-density lipoprotein (oxLDL) uptake. Resulting foam cell formation leads to lipid-rich lesions within arteries. We designed amphiphilic macromolecules (AMs) to inhibit these processes by competitively blocking oxLDL uptake via SRs, potentially arresting atherosclerotic development. In this study, we investigated the impact of replacing ester linkages with ether linkages in the AM hydrophobic domain. We hypothesized that ether linkages would impart flexibility for orientation to improve binding to SR binding pockets, enhancing anti-atherogenic activity. A series of tartaric acid-based AMs with varying hydrophobic chain lengths and conjugation chemistries were synthesized, characterized, and evaluated for bioactivity. 3-D conformations of AMs in aqueous conditions may have significant effects on anti-atherogenic potency and were simulated by molecular modeling. Notably, ether-linked AMs exhibited significantly higher levels of inhibition of oxLDL uptake than their corresponding ester analogues, indicating a dominant effect of linkage flexibility on pharmacological activity. The degradation stability was also enhanced for ether-linked AMs. These studies further suggested that alkyl chain length (i.e., relative hydrophobicity), conformation (i.e., orientation), and chemical stability play a critical role in modulating oxLDL uptake, and guide the design of innovative cardiovascular therapies.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, NJ, USA.
authors.forename: Dalia S
authors.initials: DS
authors.lastname: Abdelhamid
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, NJ, USA.
authors.forename: Yingyue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lewis
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA; Department of Biomedical Engineering, Rutgers University, NJ, USA.
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
authors.affiliation: Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, NJ, USA. Electronic address: keuhrich@rci.rutgers.edu.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
mesh_terms: D004987:Ethers / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D013644:Tartrates / Q000737:chemistry*
chemical_list: D004987:Ethers; D008077:Lipoproteins, LDL; D013644:Tartrates; C099252:oxidized low density lipoprotein; C029768:tartaric acid
keywords: Amphiphilic macromolecule; Atherosclerosis; Self-assembled micelle; oxLDL uptake