Pharmaceutical applications of peptidomimetics

Qabar, Maher; Urban, Ján; Sia, Charles; Klein, Michel; Kahn, Michaël

doi:10.1007/bf00131082

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…Strategies are being developed for the structure-guided design of mimetics of lead peptides, and there have been some successes reported (27)(28)(29). Notable advances include the substitution of thioether bonds in place of disulfides (28,30) and the use of R-methyl proline to stabilize turns.…”

mentioning

confidence: 99%

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

et al. 1998

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The presence of high titers of anti-cardiolipin antibodies (ACA's) of autoimmune origin, which are known to bind to plasma beta2-glycoprotein I (aka apolipoprotein H), correlates clinically with autoimmune recurrent thrombosis. Soluble beta2-glycoprotein I binds to solid-phase ACA (immobilized on a surface plasmon resonance chip) with a Kd of 1.4 microM, but if the reactants are reversed and beta2-glycoprotein I is on the solid-phase support, then the Kd is 52 nM. This 27-fold difference in affinity reflects the avidity/entropic advantage obtained for an antibody binding to an antigen that is made multivalent because it is attached to a solid phase. A mimotope of this antigen, selected from a phage display peptide library screen with an ACA, has been shown to bind to solid-phase ACA as a phage, using surface plasmon resonance. This peptide is representative of the motif from 37 peptides obtained in a previously reported phage library screen with this ACA (1). A synthetic version of this peptide, referred to as P4, has the sequence: A1G2P3C4I5L6L7A8R9D10R11C12P13G14, and binds to its selecting antibody with a Kd of 42 nM. NMR data indicate that proline-13 is present in both cis and trans configurations, and that these two geometries dramatically affect the overall tertiary structure of the molecule. The peptide lacking this proline binds severalfold better to the ACA, consistent with at least one of these structures having low affinity for binding ACA. Replacement of the arginine-9 position with a proline decreases binding affinity to ACA 10-fold. Another phage library-selected peptide has a proline in position 9, but also has a leucine in position 5, instead of isoleucine. Since its affinity for ACA is nearly as good as that for peptide P4, the phage library screening must have selected for a non-beta-branched amino acid in this position to compensate for the adverse effects of the arginine-9 to proline-9 substitution. The solution structure of a modified version of the antibody-selected phage peptide P4 with the central proline was determined. This peptide has one turn comprised of Ala-Pro-Asp-Arg, with the proline peptide bond in the cis configuration, and another turn that contains the disulfide and adjacent residues. If the disulfide is replaced by a thioether, and the central proline by an alpha-methyl proline, in an attempt to make the peptide more biologically stable, there is little adverse effect on affinity for ACA. The thioether bond/turn is fairly well defined with a Calpha to Calpha separation of 4.9 +/- 0.8 A. The alpha-methyl proline adopts the trans configuration, and this central Ala-(alpha-methyl-Pro)-Asp-Arg turn adopts a distorted type I turn conformation with a probable i to i+3 hydrogen bond. Modeling studies suggest that the proline peptide bond configuration switched from cis to trans in the presence of the alpha-methyl group on proline because of steric hindrance with the beta-carbon of the preceding residue. Overall, this peptidomimetic molecule is structurally very similar to the peptid...

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confidence: 99%

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

et al. 1998

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“…For example, the erythropoietin (EPO) mimetic identified from phage display do not have any homology with EPO, but able to mimic the hormone function [100]. In recent years, there has been a significant progress in the field of peptide chemistry and now peptide mimetics can be used as a template, and through iterations that reduce size and increase biological activity, may lead to viable therapeutic reagents [3,41,42,43,48,96,101,102,103,104,105,106,107,108,109]. …”

Section: Structure Of Immunoglobulinmentioning

confidence: 99%

Structure Based Antibody-Like Peptidomimetics

Murali

Greene

2012

Pharmaceuticals

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Biologics such as monoclonal antibodies (mAb) and soluble receptors represent new classes of therapeutic agents for treatment of several diseases. High affinity and high specificity biologics can be utilized for variety of clinical purposes. Monoclonal antibodies have been used as diagnostic agents when coupled with radionuclide, immune modulatory agents or in the treatment of cancers. Among other limitations of using large molecules for therapy the actual cost of biologics has become an issue. There is an effort among chemists and biologists to reduce the size of biologics which includes monoclonal antibodies and receptors without a reduction of biological efficacy. Single chain antibody, camel antibodies, Fv fragments are examples of this type of deconstructive process. Small high-affinity peptides have been identified using phage screening. Our laboratory used a structure-based approach to develop small-size peptidomimetics from the three-dimensional structure of proteins with immunoglobulin folds as exemplified by CD4 and antibodies. Peptides derived either from the receptor or their cognate ligand mimics the functions of the parental macromolecule. These constrained peptides not only provide a platform for developing small molecule drugs, but also provide insight into the atomic features of protein-protein interactions. A general overview of the reduction of monoclonal antibodies to small exocyclic peptide and its prospects as a useful diagnostic and as a drug in the treatment of cancer are discussed.

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“…In some cases, this strategy led to the production of analogues with advantageous biological and functional properties. The generation of structural mimics related to neuropeptides, peptide hormones, peptide antibiotics, or more recently peptides with potential use in vaccination has thus attracted considerable attention ( − ). The modifications introduced into peptides are for example the replacement of l -amino acid by d -amino acid residues or by unnatural ones and/or the modification of peptide bonds.…”

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confidence: 99%

Structure of Antibody-Bound Peptides and Retro−Inverso Analogues. A Transferred Nuclear Overhauser Effect Spectroscopy and Molecular Dynamics Approach^,

et al. 2001

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The three-dimensional structures of the two L-peptides, H-CGGIRGERA-OH, called L(A), and H-CGGIRGERG-OH, called L(G), corresponding or close to the IRGERA sequence present in the C-terminal region (residues 130-135) of histone H3, and their retro-inverso analogues HO-mAreGriGGC-NH2, called RI(mA), and HO-mGreGriGGC-NH2, called RI(mG), have been studied by two-dimensional 1H NMR and molecular dynamics calculations in association with a monoclonal antibody generated against L(A). At 25 degrees C, the affinity constants of the monoclonal antibody with respect to RI(mA) and RI(mG) were 75- and 270-fold higher than those measured with the homologous L(A) and L(G) peptides, respectively. Due to the spontaneous epimerization of the mA malonic residue, RI(mA) gave rise to two sets of resonances. With regard to the NH amide region, one set was similar to that for RI(mG) while the second was similar to those for the parent L-peptides L(A) and L(G). The antibody-bound conformations of the two couples of L- and retro-inverso peptides have been analyzed using molecular modeling calculations based on the transferred NOE interproton distances. Folded structures appeared in both cases with a type II' beta-turn in the parent GGIR sequence and a type I' beta-turn in the retro-inverso reGr sequence.

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Pharmaceutical applications of peptidomimetics

Cited by 6 publications

References 22 publications

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

Structure Based Antibody-Like Peptidomimetics

Structure of Antibody-Bound Peptides and Retro−Inverso Analogues. A Transferred Nuclear Overhauser Effect Spectroscopy and Molecular Dynamics Approach^,

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Pharmaceutical applications of peptidomimetics

Cited by 6 publications

References 22 publications

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

Structural Characterization and Optimization of Antibody-Selected Phage Library Mimotopes of an Antigen Associated with Autoimmune Recurrent Thrombosis

Structure Based Antibody-Like Peptidomimetics

Structure of Antibody-Bound Peptides and Retro−Inverso Analogues. A Transferred Nuclear Overhauser Effect Spectroscopy and Molecular Dynamics Approach,

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Structure of Antibody-Bound Peptides and Retro−Inverso Analogues. A Transferred Nuclear Overhauser Effect Spectroscopy and Molecular Dynamics Approach^,