Bioorganic & Medicinal Chemistry 2002-10-01

Incorporation of (2S,3S) and (2S,3R) beta-methyl aspartic acid into RGD-containing peptides.

Silke Schabbert, Michael D Pierschbacher, Ralph Heiko Mattern, Murray Goodman

Index: Bioorg. Med. Chem. 10(10) , 3331-7, (2002)

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Abstract

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.