title: Sidedness of interfacial arginine residues and anti-atherogenicity of apolipoprotein A-I mimetic peptides.
abstract: To test the hypothesis that sidedness of interfacial arginine (Arg) in apoA-I mimetic peptides, similar to that observed in apoA-I (Bashtovyy, D. et al. 2011. Sequence conservation of apolipoprotein A-I affords novel insights into HDL structure-function. J. Lipid Res. 52: 435-450.), may be important for biological activity, we compared properties of 4F and analogs, [K⁴,¹⁵>R]4F and [K⁹,¹³>R]4F, with Lys>Arg substitutions on the right and left side, respectively, of the 4F amphipathic helix. Intraperitoneal administration of these peptides into female apoE null mice (n = 13 in each group) reduced en face lesions significantly compared with controls; 4F and [K⁴,¹⁵>R]4F were equally effective whereas [K⁹,¹³>R]4F was less effective. Turnover experiments indicated that [K⁴,¹⁵>R]4F reached the highest, whereas [K⁹,¹³>R]4F had the lowest, plasma peak levels with a similar half life as the [K⁴,¹⁵>R]4F analog. The half life of 4F was two times longer than the other two peptides. The order in their abilities to associate with HDL in human plasma, generation of apoA-I particles with pre-β mobility from isolated HDL, lipid associating ability, and sensitivity of lipid complexes to trypsin digestion was: 4F>[K⁴,¹⁵,>R]4F>[K⁹,¹³>R]4F. These studies support our hypothesis that the sidedness of interfacial Arg residues in the polar face of apoA-I mimetics results in differential biological properties.
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Nayyar
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294. Electronic address: vmishra@uab.edu.
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Shaila P
authors.initials: SP
authors.lastname: Handattu
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.affiliation: Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Ronald
authors.initials: R
authors.lastname: Shin
authors.affiliation: Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: David T
authors.initials: DT
authors.lastname: McPherson
authors.affiliation: Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Champion C S
authors.initials: CCS
authors.lastname: Deivanayagam
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: David W
authors.initials: DW
authors.lastname: Garber
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.affiliation: The Atherosclerosis Research Unit, Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D001120:Arginine / Q000737:chemistry*; D043303:Aryldialkylphosphatase / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D055598:Chemical Phenomena; D002784:Cholesterol / Q000097:blood; D005260:Female; D017353:Gene Deletion; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D057786:Peptidomimetics / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010713:Phosphatidylcholines / Q000378:metabolism; D017433:Protein Structure, Secondary; D058767:Protein Unfolding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000097:blood; D053835:Unilamellar Liposomes / Q000378:metabolism
chemical_list: C468114:1-palmitoyl-2-arachidonyl-3-phosphorylcholine; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D057786:Peptidomimetics; D010713:Phosphatidylcholines; D017382:Reactive Oxygen Species; D053835:Unilamellar Liposomes; D001120:Arginine; D002784:Cholesterol; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse; D019791:Guanidine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine