Conformational Biased Peptides

Cyclization of peptides improves stability against proteases while affording conformational constraints that may enhance inhibitory potency. Research teams at M.D. Anderson and the University of Arizona have explored the efficacy of this structurally distinct class of active site-directed protein kinase inhibitors.

Lam and his colleagues have shown that the Tyr-Ile-Tyr-Gly-Ser-Phe-Lys-amide motif serves as an effective Src substrate (Lam et al. 1995) and that the peptide might bind to the active site in the form of a b-turn (Lou et al. 1997). In order to assess the reasonableness of this notion, Lam, Hruby, and their coworkers prepared a series of disulfide bridge-cyclized inhibitory peptides that target Src (Alfaro-Lopez et al. 1998). In addition, these investigators took advantage of the observation that 2-naphthylalanine (Sect. 11) serves as a nonphosphorylatable tyrosine mimetic (Wu et al. 1996).

Compound 27 exhibits an IC50 of 1.6 |iM. Interestingly, and somewhat surprisingly, potency was further improved by tenfold when the naphthy-lalanine was replaced with 3-iodotyrosine (28). This observation stands in marked contrast to the ineffectiveness of 3-iodotyrosine as a tyrosine mimetic in an EGFR-targeted inhibitory peptide (Fry et al. 1994). Peptide 28 is not only an effective Src kinase inhibitor but also exhibits impressive selectivity in favor of Src versus other Src kinase family members (20-fold versus

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