Incorporation of (2S,3S) and (2S,3R) beta-methyl aspartic acid into RGD-containing peptides.
We report the synthesis and biological activity of a series of side-chain-constrained RGD peptides containing the (2S,3R) or (2S,3S) beta-methyl aspartic acid within the RGD sequence. These compounds have been assayed for binding to the integrin receptors alpha(IIb)beta3 and alpha(v)beta3 and the results demonstrate the importance of the side-chain orientation of this particular residue within the RGD sequence. Based on our findings, the (2S,3S) beta-methylated analogues of our RGD sequences maintain their binding potency to the integrin receptors while the (2S,3R) beta-methylated analogues exhibit a drastically reduced binding affinity. Our studies demonstrate that the three-dimensional orientation of the aspartyl side chain is a very important parameter for integrin binding and that small changes that affect the side-chain orientations give rise to drastic changes in binding affinity. These results provide important information for the design of more potent RGD mimetics.
Schabbert
Silke
S
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093-0343, USA.
Pierschbacher
Michael D
MD
Mattern
Ralph Heiko
RH
Goodman
Murray
M
D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020128:Inhibitory Concentration 50; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C018934:3-methylaspartic acid; D001224:Aspartic Acid