Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Mantzourani, Efi; Laimou, Despoina; Matsoukas, Minos‐Timotheos; Tselios, Theodore

doi:10.2174/187152308786847799

Cited by 14 publications

(9 citation statements)

References 129 publications

(123 reference statements)

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“…This may also explain their antagonistic versus agonistic activity. Such differences in the binding motifs between linear and cyclic agonists and antagonists analogues of MBP 87-99 epitope were also shown in our previous work [19][20][21][22][23][24][25][26].…”

Section: Resultssupporting

confidence: 83%

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Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) with Phe [MBP(83-99) (Phe(91))] or Tyr [MBP(83-99) (Tyr(91))], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP(83-99) epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP(83-99) immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Section: Resultssupporting

confidence: 83%

“…NMR spectroscopy is coupled with MD simulations to study the binding motif of the altered peptide epitopes of MBP 83-99 with HLA-DR2 [19][20][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Potamitis

Matsoukas

Tselios

et al. 2011

J Comput Aided Mol Des

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“…Their great diversity in terms of size, shape, and chemical functionalities results in their usefulness in a variety of biological functions 1; thus, peptides play a role in many applications. For example, peptides are emerging as a novel class of therapeutic agents in the pharmaceutical field 2. In comparison to traditional drugs consisting of small molecules, peptides present numerous advantages, such as better efficiency, selectivity, and specificity, as well as lower toxicity because amino acids are the main degradation products 3, 4.…”

Section: Introductionmentioning

confidence: 99%

Comparison of columns packed with porous sub‐2 μm particles and superficially porous sub‐3 μm particles for peptide analysis at ambient and high temperature

Ruta

Guillarme

Rudaz

et al. 2010

J of Separation Science

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The objective of this study was to evaluate various chromatographic approaches for peptide analysis. Initially, the ultra-HPLC (UHPLC) strategy, which consists of using columns packed with sub-2 microm particles at a maximal pressure of 1000 bar, was tested. To limit the backpressure generated by small particles, columns packed with superficially porous sub-3 microm particles (fused-core technology) that should theoretically improve mass transfer, particularly beneficial for large biomolecules, were investigated. To evaluate these claims, kinetic plots were constructed in both isocratic and gradient modes at ambient and elevated temperature (up to 90 degrees C). For peptide analysis, both UHPLC and fused-core technologies showed a significant gain in peak capacity when compared with conventional HPLC using 5 mum particles and monolithic supports. Additionally, it has been shown that high temperature was of utmost interest to further improve kinetic performance and peak shape due to the improvement of secondary interaction kinetics. Finally, the best conditions developed for UHPLC using the gradient kinetic plot methodology were applied to the analysis of a complex tryptic digest of various proteins. The expected and experimental peak capacity values obtained were similar. In addition, the resolving power of UHPLC at 60 degrees C was appropriate for resolving complex mixtures of peptides.

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“…Moreover, the intramolecular hydrogen bonds between the Gln 3 and Arg 5 (Fig. 7) for the [20,[26][27][28][29][30].…”

Section: Resultsmentioning

confidence: 99%

Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

Laimou

Lazoura

Troganis

et al. 2011

J Comput Aided Mol Des

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Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln(3) residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-A(u) complex, has a different orientation in the mutated analogues especially in the Ac-MBP(1-11)[4A] peptide. In particular the side chain of Gln(3) is not solvent exposed as for the native Ac-MBP(1-11) and it is not available for interaction with the TCR.

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Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Cited by 14 publications

References 129 publications

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

Comparison of columns packed with porous sub‐2 μm particles and superficially porous sub‐3 μm particles for peptide analysis at ambient and high temperature

Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

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