SAR for MHC class II binding tetrapeptides: Correlation with potential binding site

Cunningham, Barry R.; Rivetna, Meheryar N.; Tolman, Richard L.; Flattery, Stacey J; Nichols, Elizabeth A.; Schwartz, Cheryl D.; Wicker, Linda S.; Hermes, Jeffrey D.; Jones, A. Brian

doi:10.1016/s0960-894x(96)00579-3

Cited by 7 publications

(3 citation statements)

References 6 publications

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“…Truncation Series. Recent reports − have cited evidence that the heptapeptide length requirement for binding to two of the RA-linked alleles is not absolute. We have observed that the position 7 residue could be removed with a modest effect on binding activity, but (vide infra) the activity in cellular assays did not always follow this trend.…”

Section: Design and Sar Of Peptide Analoguesmentioning

confidence: 99%

Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

et al. 2000

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Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.

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Section: Design and Sar Of Peptide Analoguesmentioning

confidence: 99%

Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

et al. 2000

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“…Based on the MCSS molecular probe maps and experimental observations that tetrapeptides thought to occupy pockets P1 through P4 of MHC Class II proteins inhibit binding of full length peptides [103], the library was designed to focus on P1 through P4 of the binding groove as well as a region near the break in the a 1 -helix bounding the binding groove (HLA-DR4 residues S53, F54, and E55) and adjacent to P1 and P2. Initial visual inspection of the MCSS molecular probe maps suggested a framework for the library.…”

Section: Monomer Selectionmentioning

confidence: 99%

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

Evensen

Joseph‐McCarthy

Weiss

et al. 2007

J Comput Aided Mol Des

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Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these ''random'' methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.

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“…These results suggested that the mimetics were able to survive and compete with protein-derived antigenic peptide fragments in the endosomal compartment where the MHC molecules are loaded. Other studies have been reported in which the HLA-DR1 structure was used to design inhibitors of in vitro peptide binding to HLA-DR1 that resemble tetrapeptides − or longer peptidic ligands . Inhibitors of MHC class I molecules have also been reported. − …”

Section: Introductionmentioning

confidence: 99%

The Crystal Structure of a Pyrrolinone−Peptide Hybrid Ligand Bound to the Human Class II MHC Protein HLA-DR1

et al. 2000

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The X-ray crystal structure of a complex between the human class II major histocompatibility complex (MHC) protein HLA-DR1 and a bispyrrolinone−peptide hybrid ligand has been determined to 2.7 Å resolution. The bispyrrolinone segment of the ligand closely mimics the polyproline type II conformation of peptide ligands bound to class II MHC molecules, emphasizing the considerable versatility of this peptidomimetic scaffold. Most hydrogen bonds conserved in all peptide/class II complexes are formed, and the side chains of the bispyrrolinone segment project into the same spaces as those occupied by side chains of bound peptides. Molecular modeling used in the design of the hybrid ligand was remarkably accurate in predicting the observed molecular interactions.

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SAR for MHC class II binding tetrapeptides: Correlation with potential binding site

Cited by 7 publications

References 6 publications

Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

The Crystal Structure of a Pyrrolinone−Peptide Hybrid Ligand Bound to the Human Class II MHC Protein HLA-DR1

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