Oxpholipin 11D: an anti-inflammatory peptide that binds cholesterol and oxidized phospholipids.
BACKGROUND
Many gram-positive bacteria produce pore-forming exotoxins that contain a highly conserved, 12-residue domain (ECTGLAWEWWRT) that binds cholesterol. This domain is usually flanked N-terminally by arginine and C-terminally by valine. We used this 14-residue sequence as a template to create a small library of peptides that bind cholesterol and other lipids.


RESULTS
Several of these peptides manifested anti-inflammatory properties in a predictive in vitro monocyte chemotactic assay, and some also diminished the pro-inflammatory effects of low-density lipoprotein in apoE-deficient mice. The most potent analog, Oxpholipin-11D (OxP-11D), contained D-amino acids exclusively and was identical to the 14-residue design template except that diphenylalanine replaced cysteine-3. In surface plasmon resonance binding studies, OxP-11D bound oxidized (phospho)lipids and sterols in much the same manner as D-4F, a widely studied cardioprotective apoA-I-mimetic peptide with anti-inflammatory properties. In contrast to D-4F, which adopts a stable alpha-helical structure in solution, the OxP-11D structure was flexible and contained multiple turn-like features.


CONCLUSIONS
Given the substantial evidence that oxidized phospholipids are pro-inflammatory in vivo, OxP-11D and other Oxpholipins may have therapeutic potential.
Ruchala
Piotr
P
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. pruchala@mednet.ucla.edu
Navab
Mohamad
M
Jung
Chun-Ling
CL
Hama-Levy
Susan
S
Micewicz
Ewa D
ED
Luong
Hai
H
Reyles
Jonathan E
JE
Sharma
Shantanu
S
Waring
Alan J
AJ
Fogelman
Alan M
AM
Lehrer
Robert I
RI
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism*; D015195:Drug Design; D005098:Exotoxins / Q000737:chemistry*; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism*; D011485:Protein Binding
D000893:Anti-Inflammatory Agents; D001426:Bacterial Proteins; D005098:Exotoxins; D019151:Peptide Library; D010455:Peptides; D010743:Phospholipids; D002784:Cholesterol