A peptide inhibitor of cholesteryl ester transfer protein identified by screening a bacteriophage display library.
We screened a bacteriophage display library of random decapeptides to identify peptide inhibitors of cholesteryl ester transfer protein (CETP). After affinity selection against CETP, bacteriophage-infected Escherichia coli were plated at clonal density and 36 random clones were isolated. Analysis of the relevant portion of the bacteriophage DNA from a group of 12 clones that had a relatively high affinity for CETP revealed that the corresponding amino acid sequences of the displayed peptides exhibited an ... Xaa-Arg-Met-Arg-Tyr-Xaa ... composite motif. Based on those results, decapeptides from this group were synthesized and one of them, DP1 (NH2-VTWRMWYVPA-COOH), inhibited CETP-catalyzed transfer of cholesteryl esters and triglycerides. Amino- and carboxy-terminal truncations of DP1 demonstrated that the original decapeptide could be reduced to a pentapeptide without loss of either its ability to bind to CETP or its ability to inhibit CETP-mediated lipid transfer. That pentapeptide, NH2-WRMWY-COOH (WRMWY, PNU-107368E), binds directly to CETP and its inhibition is consistent with that of a competitive inhibitor of CETP with a Ki of 164 microM. WRMWY or modified versions of this peptide may be useful in studying the interactions between CETP and plasma lipoproteins.
Bonin
P D
PD
Cancer Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49007-4940, USA.
Bannow
C A
CA
Smith
C W
CW
Fischer
H D
HD
Erickson
L A
LA
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism; D003090:Coliphages / Q000235:genetics*; D006224:Cricetinae; D004926:Escherichia coli / Q000821:virology; D006023:Glycoproteins; D008252:Macaca fascicularis; D009842:Oligopeptides / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding; D014280:Triglycerides / Q000378:metabolism
D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D009842:Oligopeptides; D019151:Peptide Library; D014280:Triglycerides