Antiplatelet "hybrid" peptides analogous to receptor recognition domains on .gamma. and .alpha. chains of human fibrinogen

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Abstract
Platelet receptor recognition domains are located on the .gamma. and .alpha. chains of human fibrinogen. The former encompasses residues 400-411 [Kloczewiak, M., Timmons, S., Lukas, T.J., and Hawiger, J. (1984) Biochemistry 23, 1767], and the latter is present in two loci on the .alpha. chain (.alpha.95-97 and .alpha.572-574) [Hawiger, J., Kloczewiak, M., Bednarek, M. A., and Timmons, S. (1989) Biochemistry (first of three papers in this issue)]. Peptide .gamma.400-411 (HHLGGAKQAGDV) inhibited aggregation of ADP-treated platelets mediated not only, by .gamma.-chain but also by .alpha.-chain multimers. Peptide .alpha.572-575 (RSDS) inhibited aggregation of platelets mediated by .alpha.-chain as well as .gamma.-chain mutimers. These results indicate that the platelet receptor for fibrinogen is isospecific with regard to the domain present on .alpha. and .gamma. chains. Subsequent "checkerboard" analysis of combinations of .gamma.-400-411 and .alpha.572-575 showed that the inhibitory effect toward binding of 125I-fibrinogen was additive rather than synergistic. Next, a series of "hybrid" peptides was constructed in which the .alpha.-chain sequence RGDE (.alpha.95-98) replaced the carboxy-terminal segment of .gamma.-408-411. The dodecapeptide HHLGGAKQRGDF was inhibitory with concentration, causing 50% inhibition of binding (IC50) at 6 .mu.M, 5 times more potent that .gamma.400-411. The shorter peptides AKQRGDF and KQRGDF were also more inhibitory than .gamma.-400-411. The second series of hybrid peptides was constructed with the .alpha.-chain sequence RGDS preceding the sequence of .gamma.-400-411 or sequence RGDV following it. The hybrid peptides YRGDSQHLGGAKQAGDV and HHLGGAKQAGDVGRGDV had the same reactivity toward platelet receptors as .gamma.-400-411. Alternatively, the hybrid peptide HHLGGAKQAGDSRGDV was 3 times more potent (IC50 = 10 .mu.M). Hybrid peptides mimicking the .gamma.-chain domain represent a new class of inhibitors with enhanced potency toward the platelet receptor for fibrinogen.

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