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J. Biol. Chem., Vol. 279, Issue 25, 26509-26517, June 18, 2004

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Aromatic Residue Position on the Nonpolar Face of Class A Amphipathic Helical Peptides Determines Biological Activity^*

Geeta Datta, Raquel F. Epand, Richard M. Epand, Manjula Chaddha, Matthew A. Kirksey, David W. Garber, Sissel Lund-Katz¶, Michael C. Phillips¶, Susan Hama||, Mohamad Navab||, Alan M. Fogelman||, Mayakonda N. Palgunachari, Jere P. Segrest, and G. M. Anantharamaiah**

From the Departments of Medicine, Biochemistry and Molecular Genetics and the Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, Alabama 35294, the Department of Biochemistry, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada, ^¶The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, and the ^||Department of Medicine and the Atherosclerosis Research Unit, UCLA Cardiology, UCLA, Los Angeles, California 90095

The apolipoprotein A-I mimetic peptide 4F (Ac-DWFKAFYDKVAEKFKEAF-NH₂), with four Phe residues on the nonpolar face of the amphipathic -helix, is strongly anti-inflammatory, whereas two 3F analogs (3F³ and 3F¹⁴) are not. To understand how changes in helix nonpolar face structure affect function, two additional 3F analogs, Ac-DKLKAFYDKVFEWAKEAF-NH₂ (3F-1) and Ac-DKWKAVYDKFAEAFKEFL-NH₂ (3F-2), were designed using the same amino acid composition as 3F³ and 3F¹⁴. The aromatic residues in 3F-1 and 3F-2 are near the polar-nonpolar interface and at the center of the nonpolar face of the helix, respectively. Like 4F, but in contrast to 3F³ and 3F¹⁴, these peptides effectively inhibited lytic peptide-induced hemolysis, oxidized phospholipid-induced monocyte chemotaxis, and scavenged lipid hydroperoxides from low density lipoprotein. High pressure liquid chromatography retention times and monolayer exclusion pressures indicated that there is no direct correlation of peptide function with lipid affinity. Fluorescence studies suggested that, although the peptides bind phospholipids similarly, the Trp residue in 4F, 3F-1, and 3F-2 is less motionally restricted than in 3F³ and 3F¹⁴. Based on these results and molecular modeling studies, we propose that the arrangement of aromatic residues in class A amphipathic helical molecules regulates entry of reactive oxygen species into peptide-phospholipid complexes, thereby reducing the extent of monocyte chemotaxis, an important step in atherosclerosis.

Received for publication, December 30, 2003 , and in revised form, April 8, 2004.

^* This work was supported in part by National Institutes of Health Grants PO1 HL34343, 30568, and 22633 and Canadian Institutes of Health Research Grant MT-7654. M. N., S. H., A. M. F., and G. M. A. are principals in Bruin Pharma, a start-up biotech company. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: 1808 7th Ave. S., DREB 640, Department of Medicine, UAB Medical Center, Birmingham, AL 35294. Tel.: 205-934-1494; E-mail: Ananth{at}uab.edu.

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