Incorporation of (2S,3S) and (2S,3R) β-Methyl aspartic acid into RGD-Containing peptides Original Research Article

We report the synthesis and biological activity of a series of side-chain-constrained RGD peptides containing the (2S,3R) or (2S,3S) β-methyl aspartic acid within the RGD sequence. These compounds have been assayed for binding to the integrin receptors αIIbβ3 and αvβ3 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) β-methylated analogues of our RGD sequences maintain their binding potency to the integrin receptors while the (2S,3R) β-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.