Incorporation of thioether building blocks into an alphavbeta3-specific RGD peptide: synthesis and biological activity.
We report the design, synthesis, and binding affinities of a family of thioether analogues of the alpha(v)beta(3)-specific compound c[(Mpa)RGDD(tBuG)C]-NH(2). The synthesis of the thioether building blocks is scalable and produced the desired products in good yields. The linear peptides were synthesized on solid supports, followed by cyclization in solution. Our analogues demonstrate interesting binding data to the isolated receptors. In particular, the peptide c[NH-Arg-Gly-Asp-Asp-(tBuG)-Cys(S-CH(2)-CO)]NH(2) (1) exhibits differences in binding when compared to the parent compound and demonstrates potent affinity to the alpha(v)beta(3) and alpha(5)beta(1) receptors while having reduced binding to the alpha(IIb)beta(3) receptor. This result combined with the replacement of the disulfide with a thioether makes this compound interesting for further development.
Kelleman
Audrey
A
Department of Chemistry and Biochemistry University of California San Diego, La Jolla, CA 92093-0343, USA.
Mattern
Ralph-Heiko
RH
Pierschbacher
Michael D
MD
Goodman
Murray
M
D000595:Amino Acid Sequence; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013440:Sulfides / Q000737:chemistry*
D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D013440:Sulfides; C047981:arginyl-glycyl-aspartic acid