Novel, potent calmodulin antagonists derived from an all‐<scp>d</scp> hexapeptide combinatorial library that inhibit <i>in vivo</i> cell proliferation: activity and structural characterization

Blondelle, Sylvie E.; Crooks, Ema T.; Aligué, Rosa; Agell, Neus; Bachs, Oriol; Esteve, Vicent; Tejero, Roberto; Celda, Bernardo; Pastor, María Teresa; Pérez‐Payá, Enrique

doi:10.1034/j.1399-3011.2000.00162.x

Cited by 11 publications

(4 citation statements)

References 46 publications

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“…Interproton distances for the XVMe peptide were obtained by measuring cross‐peak volumes in the ROESY spectra of oligopeptides. Three upper bound distances (3, 4, and 5 Å) were considered, corresponding to three different NOE cross‐peak intensities (strong, medium, and weak, respectively) 14–17…”

Section: Methodsmentioning

confidence: 99%

Solution structure of a D,L‐alternating oligonorleucine as a model of double‐stranded antiparallel β‐helix

2002

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Conformational characteristics of alternating D,L linear peptides are of particular interest because of their capacity to form transmembrane channels with different transport properties, as some natural antibiotics do. Single- and double-stranded beta-helical structures are common for alternating D,L peptides. The stability of the beta-helix depends on several structural factors, such as the backbone peptide length, type and position of side chains, and nature of terminal groups. The NMR and molecular dynamics solution conformation of a synthetic alternating D,L-oligopeptide with 15 norleucines (XVMe) has been used as a model to get insight in to the conformational features of double-stranded beta-helix structures. The NH chemical shift values (delta(NH)) and long-range nuclear Overhauser effects (NOE) cross peaks, in particular interstrand connectivities, clearly point to an antiparallel double-stranded beta-helix for the XVMe major conformation in solution. An extensive set of distances (from NOE cross peaks) and H-bonds (from delta(NH)) has been included in the molecular dynamics calculations. The experimental NMR data and theoretical calculations clearly indicate that the most probable conformation of XVMe in solution is a double-strand antiparallel beta(5.6) increasing decreasing-helix structure.

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Section: Methodsmentioning

confidence: 99%

Solution structure of a D,L‐alternating oligonorleucine as a model of double‐stranded antiparallel β‐helix

2002

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“…Normally, such a change in the stereochemistry of side chains should disrupt a stereospecific ligand-receptor interface. There are only a limited number of cases reported in the literature where both D-and L-peptide enantiomers recognize the same receptors, such as L-and Dpeptide ligands for calmodulin (50,51), L-and D-peptides derived from type IV collagen that bind the ␣ 3 ␤ 1 integrin (52,53), and L-and D-peptide ligands for the co-chaperone DnaJ (Hsp40) (54). However, to our knowledge of current literature, CXCR4 binding by D-and L-peptide ligands derived from natural chemokines as reported here is unprecedented for chemokine receptors and membrane proteins of the GPCR family.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Stereochemistry of CXCR4-Peptide Recognition and Inhibiting HIV-1 Entry with d-Peptides Derived from Chemokines

Zhou¹,

Luo²,

Luo³

et al. 2002

Journal of Biological Chemistry

119

144

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The chemokine receptor CXCR4 is critical for many biological functions, such as B-cell lymphopoiesis, regulation of neuronal cell migration, and vascular development (1-3). In addition, CXCR4 together with another chemokine receptor CCR5 are two principal co-receptors for the cellular entry of the human immunodeficiency virus type 1 (HIV-1) 1 (4 -7). The stromal cell-derived factor-1 (SDF-1␣) is the only known natural ligand of CXCR4 and plays important roles in migration, proliferation, and differentiation of leukocytes (8, 9). The viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus 8 (10) is an antagonistic chemokine ligand of CXCR4 (11, 12). vMIP-II also interacts with other chemokine receptors such as CCR5 and CCR3 and inhibits HIV-1 entry mediated by these co-receptors.CXCR4 and other chemokine receptors belong to the superfamily of seven transmembrane G-protein-coupled receptors (GPCRs) (13). These membrane proteins transmit signals from extracellular ligands to intracellular biological pathways via heterotrimeric G-proteins and have been a major class of therapeutic targets for a wide variety of human diseases (14). As such, characterizing the mechanism of biological recognition between these receptors and their ligands is essential for understanding the physiological or pathological processes that they mediate and devising novel strategies for clinical intervention. For CXCR4, studies have been carried out by a number of laboratories using chimeric chemokine receptors and site-specific mutants to study multiple domains of CXCR4 that are important for interacting with chemokine ligands and HIV-1 (15-23). However, because there is no high resolution crystal structure available for CXCR4 (or any other chemokine receptor) alone or complexed with ligands, the structural and biochemical basis of ligand binding and signaling through these important membrane receptors remains poorly understood.To further define the structure-function relationship of the chemokine receptor-ligand interaction, theoretical computer modeling and site-directed mutagenesis were combined to predict plausible structural models for chemokine receptors and their complexes with ligands, such as interleukin-8 receptor ␤ (24) and CCR5 (25,26). Structural models of CXCR4 and its complex with ligands were also proposed (27, 28). Complementary to modeling and mutational analyses of the receptors,

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“…The total number of libraries cited was 284, comparable to the 297 figure for 1999, bringing the cumulative total to over 1250 libraries published since 1992 − …”

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confidence: 80%

Comprehensive Survey of Combinatorial Library Synthesis: 2000

Dolle

2001

J. Comb. Chem.

197

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An exhaustive compilation of biologically active libraries covering the years 1992-1997 was presented in a previous review [1a]. In that review, libraries were divided among 4 major categories, including those active against proteases, non-proteolytic enzymes, Gprotein coupled receptors, and non-G-protein coupled receptors. A generic structure for each library was provided as well as the structure of the most active member. The number of biologically active libraries reported in the literature during this time period (86 total) represents <25% of the total number of published library constructs. Disclosure of library synthesis without accompanying screening data is a more common occurrence. Because these types of libraries are equally important to the practicing combinatorial chemist, it was thought that a comprehensive listing of such libraries spanning the years 1992-1997 would be a useful supplement to the previous review [1a,b].Library constructs [2-248] listed herein are relegated to one of five tables. Table 1 is entitled 'Scaffold derivatization' and includes all constructs in which a multi-functional scaffold is modified in some fashion to create a library. An example of a construct found in Table 1 would be the sequential addition of three nucleophiles to trichloropyrimidine. Table 2, entitled 'Acyclic synthesis', lists all linear constructs such as those derived from multi-component Ugi condensations.

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Novel, potent calmodulin antagonists derived from an all‐d hexapeptide combinatorial library that inhibit in vivo cell proliferation: activity and structural characterization

Cited by 11 publications

References 46 publications

Solution structure of a D,L‐alternating oligonorleucine as a model of double‐stranded antiparallel β‐helix

Solution structure of a D,L‐alternating oligonorleucine as a model of double‐stranded antiparallel β‐helix

Exploring the Stereochemistry of CXCR4-Peptide Recognition and Inhibiting HIV-1 Entry with d-Peptides Derived from Chemokines

Comprehensive Survey of Combinatorial Library Synthesis: 2000

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