The β-d-Glucose Scaffold as a β-Turn Mimetic

Activity and selectivity are typically the first considerations when designing a drug. However, absorption, distribution, metabolism, excretion, and toxicity (ADMET) are equally important considerations. Peptides can provide a combination of potent binding and exquisite selectivity, as evidenced by their pervasive use as enzymes, hormones, and signaling agents within living systems. In particular, peptidic turn motifs are key elements of molecular recognition. They may be found at the exposed surfaces of globular proteins, where they are available for binding interactions with other peptides and small molecules. However, despite these advantages, peptides often make poor drugs. The amide backbone is subject to rapid enzymatic proteolysis, resulting in short half-lives. Furthermore, the ability of the amide backbone to hydrogen bond with water restricts its ability to cross membranes and, consequentially, results in poor oral bioavailability. Accordingly, the development of nonpeptidic scaffolds that mimic peptidic turn motifs represents a promising means of converting peptidic agents into more drugable molecules. In this Account, we describe the design and synthesis of beta-turn mimetics that use a beta-D-glucose scaffold, the first use of a sugar scaffold for this purpose. Somatostatin (SRIF) is a small protein (14 amino acid residues) human hormone; a shorter (6 amino acid residues) synthetic peptide, L-363,301, is a fully peptidal agonist. These two cyclic peptides share the beta-turn motif comprising Phe(7)-Trp(8)-Lys(9)-Thr(10) (d-Trp(8) in the case of L-363,301), of which the tryptophan and lysine residues in the i + 1 and i + 2 positions, respectively, are critical for binding. In 1988, we initiated a program that tested and validated the then-novel proposition that the beta-D-glucose scaffold can mimic the beta-turn in L-363,301. The beta-D-glucose scaffold proved to be an attractive mimic of a beta-turn in part because it permits the convenient attachment of amino acid side chains via facile etherification reactions, rather than carbon-carbon bond formations; it is also an inexpensive starting material with well-defined stereochemistry. From the beginning, biological assays were used alongside physical measurements to assess the relevance of the design. Our first two synthetic targets, compounds 6 and 7, bound the SRIF receptors on benchmark (AtT-20) cells, albeit weakly, consistent with the objective of the design. Subsequently, a better ligand (8) and two congeners were found to be agonists at the SRIF receptors, providing convincing evidence that the peptide backbone is not required for receptor binding or signal transduction. The unexpectedly high level of receptor affinity of selected analogs, as well as the fortuitous discovery that our peptidomimetics were active against several chemically distinct receptors, led us to hypothesize that these monosaccharides could access multiple potential binding modes. Our later studies of this sugar scaffold confirmed this property, which we termed pseudosymmetry, whereby multiple similar but nonidentical motifs are displayed within a single analog. We propose the presence of pseudosymmetry to be an element of privilege and an advantage for lead discovery.