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

Abstract

ConspectusActivity 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 β-turn mimetics that use a β-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 β-turn motif comprising Phe 7 -Trp 8 -Lys 9 -Thr 10 (D-Trp 8 in the case of L-363,301), of which the Trp and Lys 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 β-D-glucose scaffold can mimic the β-turn in L-363,301. The β-D-glucose scaffold proved to be an attractive mimic of a β-turn in part because it permits the convenient attachment of amino acid side chains via facile etherification reactions, rather than carboncarbon bond formations; it is also an inexpensive starting material with well-defined *To whom correspondence should be addressed. rfh@sas.upenn.edu. 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 tohypothesize 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 non-identical 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. NIH Public Access IntroductionPeptides play a fundamental role in biology. However, their use as therapeutics has been limited by their poor pharmacokinetic properties. 1 Peptides are subject to proteolysis, which results in short biological half-lives even after parenteral administration....

Synthesis and Analysis of the Conformational Preferences of 5‐Aminomethyloxazolidine‐2,4‐dione Scaffolds: First Examples of β2‐ and β2, 2‐Homo‐Freidinger Lactam Analogues

“…b-Turns are common motifs in peptide structures (Figure 1), and they are very often critical to peptide conformational stability, with many interactions correlated to a variety of biological processes. [6] For instance, the prototypic Freidinger lactam dipeptides [2,4,7] have been widely used to constrain peptide conformations, stabilizing turn structures and acting as strand inducers ( Figure 1). [5] As a consequence, small scaffolds that reproduce these features have been extensively investigated to discover compounds that can mimic or disrupt turn-mediated recognition events.…”

“…[5] As a consequence, small scaffolds that reproduce these features have been extensively investigated to discover compounds that can mimic or disrupt turn-mediated recognition events. [3,6] Frequently, the side chains at some fundamental positions are not maintained, or one of the amino acids is omitted on the basis of the hypothesis that some residues play a structural rather than a recognition role; for example, Pro or Gly at position i + 1 of a b-turn. [8] However, the scaffold strategy has so far resulted in limited success with bioactive peptide ligands for which the nonpeptide or pseudopeptide scaffold itself contains most of the pharmacophore elements.…”

“…[6] For instance, the prototypic Freidinger lactam dipeptides [2,4,7] have been widely used to constrain peptide conformations, stabilizing turn structures and acting as strand inducers ( Figure 1). [6,9] Therefore, the structures of the turn mimetics may lack some relevant pharmacophores for specific targets. [3,6] Frequently, the side chains at some fundamental positions are not maintained, or one of the amino acids is omitted on the basis of the hypothesis that some residues play a structural rather than a recognition role; for example, Pro or Gly at position i + 1 of a b-turn.…”

“…An example is represented by the early Freidinger lactams (Figure 1) obtained by sacrificing the i + 1 side chain with the formation of five-to eight-membered rings. [6] As a consequence, the development of an expedient procedure with which to constrain a peptide while maintaining all of the pharmacophores is of considerable interest. [11] Furthermore, the preparation of constrained mimetics may require multistep procedures, resulting in low overall yields, and many synthetic methods lack flexibility and are therefore not suited to the introduction of diversity.…”

Protein templates in hard tissue engineering

“…Templates for tissue engineering have been built with three major protein-folding motifs: α-helices [70], β-pleated structures [52, 71–73] and collagen triple helices [74]. Exploiting the properties of these motifs has been demonstrated as a new route for novel material synthesis[83, 84]. One of the most studied motifs is leucine zipper (coiled-coil motif).…”