FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2079363605> ?p ?o ?g. }

• W2079363605 endingPage "1520" @default.
• W2079363605 startingPage "1511" @default.
• W2079363605 abstract "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 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 Phe7-Trp8-Lys9-Thr10 (d-Trp8 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 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 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." @default.
• W2079363605 created "2016-06-24" @default.
• W2079363605 creator A5035747535 @default.
• W2079363605 creator A5062506385 @default.
• W2079363605 creator A5065008454 @default.
• W2079363605 creator A5066527875 @default.
• W2079363605 creator A5072463303 @default.
• W2079363605 date "2009-07-22" @default.
• W2079363605 modified "2023-09-26" @default.
• W2079363605 title "The β-<scp>d</scp>-Glucose Scaffold as a β-Turn Mimetic" @default.
• W2079363605 cites W1965274591 @default.
• W2079363605 cites W1970555720 @default.
• W2079363605 cites W1974626719 @default.
• W2079363605 cites W1979435862 @default.
• W2079363605 cites W1981326638 @default.
• W2079363605 cites W1989199133 @default.
• W2079363605 cites W1991286793 @default.
• W2079363605 cites W1993415924 @default.
• W2079363605 cites W1995922082 @default.
• W2079363605 cites W2002474622 @default.
• W2079363605 cites W2004732735 @default.
• W2079363605 cites W2006611896 @default.
• W2079363605 cites W2007074151 @default.
• W2079363605 cites W2010051841 @default.
• W2079363605 cites W2017103045 @default.
• W2079363605 cites W2017368395 @default.
• W2079363605 cites W2034531422 @default.
• W2079363605 cites W2041559752 @default.
• W2079363605 cites W2042529958 @default.
• W2079363605 cites W2045317565 @default.
• W2079363605 cites W2051334762 @default.
• W2079363605 cites W2053036921 @default.
• W2079363605 cites W2053862201 @default.
• W2079363605 cites W2057740793 @default.
• W2079363605 cites W2059664977 @default.
• W2079363605 cites W2060531713 @default.
• W2079363605 cites W2066581720 @default.
• W2079363605 cites W2066961392 @default.
• W2079363605 cites W2078552758 @default.
• W2079363605 cites W2079983266 @default.
• W2079363605 cites W2084687677 @default.
• W2079363605 cites W2106882534 @default.
• W2079363605 cites W2120540345 @default.
• W2079363605 cites W2126533930 @default.
• W2079363605 cites W2145069916 @default.
• W2079363605 cites W2149963584 @default.
• W2079363605 cites W2152661044 @default.
• W2079363605 cites W2343434599 @default.
• W2079363605 cites W2483229476 @default.
• W2079363605 cites W2486195344 @default.
• W2079363605 cites W2916451683 @default.
• W2079363605 cites W2949760899 @default.
• W2079363605 cites W2949944806 @default.
• W2079363605 cites W2951500584 @default.
• W2079363605 cites W2951681395 @default.
• W2079363605 cites W4250058955 @default.
• W2079363605 doi "https://doi.org/10.1021/ar900020x" @default.
• W2079363605 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2764824" @default.
• W2079363605 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19624154" @default.
• W2079363605 hasPublicationYear "2009" @default.
• W2079363605 type Work @default.
• W2079363605 sameAs 2079363605 @default.
• W2079363605 citedByCount "58" @default.
• W2079363605 countsByYear W20793636052012 @default.
• W2079363605 countsByYear W20793636052013 @default.
• W2079363605 countsByYear W20793636052014 @default.
• W2079363605 countsByYear W20793636052015 @default.
• W2079363605 countsByYear W20793636052016 @default.
• W2079363605 countsByYear W20793636052017 @default.
• W2079363605 countsByYear W20793636052018 @default.
• W2079363605 countsByYear W20793636052019 @default.
• W2079363605 countsByYear W20793636052020 @default.
• W2079363605 countsByYear W20793636052021 @default.
• W2079363605 countsByYear W20793636052022 @default.
• W2079363605 crossrefType "journal-article" @default.
• W2079363605 hasAuthorship W2079363605A5035747535 @default.
• W2079363605 hasAuthorship W2079363605A5062506385 @default.
• W2079363605 hasAuthorship W2079363605A5065008454 @default.
• W2079363605 hasAuthorship W2079363605A5066527875 @default.
• W2079363605 hasAuthorship W2079363605A5072463303 @default.
• W2079363605 hasBestOaLocation W20793636052 @default.
• W2079363605 hasConcept C124790011 @default.
• W2079363605 hasConcept C132677234 @default.
• W2079363605 hasConcept C161624437 @default.
• W2079363605 hasConcept C185592680 @default.
• W2079363605 hasConcept C21951064 @default.
• W2079363605 hasConcept C2776016237 @default.
• W2079363605 hasConcept C2779281246 @default.
• W2079363605 hasConcept C31684184 @default.
• W2079363605 hasConcept C515207424 @default.
• W2079363605 hasConcept C55493867 @default.
• W2079363605 hasConcept C60984968 @default.
• W2079363605 hasConcept C71240020 @default.
• W2079363605 hasConcept C74187038 @default.
• W2079363605 hasConcept C85641259 @default.
• W2079363605 hasConceptScore W2079363605C124790011 @default.
• W2079363605 hasConceptScore W2079363605C132677234 @default.
• W2079363605 hasConceptScore W2079363605C161624437 @default.

• next