To probe the conformational requirements of loop 1 in the Pin1 WW domain, the residues at the i + 2 and i + 3 positions of a beta-turn within this loop were replaced by dPro-Gly and Asn-Gly, which are known to prefer the conformations required at the i + 1 and i + 2 positions of type II' and type I' beta-turns. Conformational specificity or lack thereof was further examined by incorporating into the i + 2 and i + 3 positions a non-alpha-amino acid-based beta-turn mimetic (4-(2'-aminoethyl)-6-dibenzofuran propionic acid residue, 1), which was designed to replace the i + 1 and i + 2 positions of beta-turns. All these Pin WW variants are monomeric and folded as discerned by analytical ultracentrifugation, NMR, and CD. They exhibit cooperative two-state transitions and display thermodynamic stability within 0.5 kcal/mol of the wild-type WW domain, demonstrating that the acquisition of native structure and stability does not require a specific sequence and, by extension, conformation within loop 1. However, it could be that these loop 1 mutations alter the kinetics of antiparallel beta-sheet folding, which will be addressed by subsequent kinetic studies.

A convergent, stereocontrolled route to either antipode of the cell adhesion inhibitor, peribysin E, has been achieved from carvone. Highlights of the synthesis include a Diels−Alder reaction to generate a cis-decalin framework, followed by semipinacol-type ring contraction to secure the stereochemistry of the C7 quaternary center. Potential mechanistic pathways for the critical ring contraction were studied through deuterium incorporation studies. In addition, an optimized olefin isomerization/Saegusa oxidation protocol is described for the conversion of [4+2] cycloadducts of 2-(trialkylsilyloxy)-1,3-dienes to 1,6(2H,7H)-naphthalenediones, having stereochemical arrangements not accessible via conventional Robinson annulation protocols. Finally, the ability to independently prepare either enantiomer of peribysin E from the corresponding antipode of carvone led to a reassignment of the absolute configuration of peribysin E.

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....

The right way round: Peribysin E, a naturally occurring adhesion inhibitor, has been synthesized and, as a result, its absolute configuration reassigned. The natural and nonnatural enantiomers can be reached starting from (R)‐ or (S)‐carvone, respectively. A key step is the ring contraction of 1 to 2 (see scheme, TBS=tert‐butyldimethylsilyl, TES=triethylsilyl).