Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

Falcioni, Fiorenza; Ito, Kouichi; Vidovic, Damir; Belunis, Charles; Campbell, Robert M.; Berthel, Steven J.; Bolin, David; Gillespie, Paul; Huby, Nicholas; Olson, Gary L.; Sarabu, Ramakanth; Guenot, Jeanmarie; Madison, V.; Hammer, Jürgen; Sinigaglia, Francesco; Steinmetz, Michael; Nagy, Zoltán Á.

doi:10.1038/9865

Cited by 53 publications

(44 citation statements)

References 37 publications

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“…These prAPL are lysosomal protease-resistant, highaffinity binding peptides because the anchor residues for MHC class II (HLA-DRB1*1501) are not changed, and they resulted in mitigated T cell activation. The exchange of one amino acid (K91 to P91) is sufficient to antagonize T cell proliferation because H88, F89 and K91 are TCR contact sites and important for T cell activation, which correlates with published data [114].…”

Section: Generation Of Protease-resistant Aplsupporting

confidence: 77%

“…In addition, methylated amino acids can be incorporated into an APL to protect it from degradation by CatB, CatD and CatH. The resulting APL inhibit T cell activation [113,114]. In addition to protease resistance being beneficial for effective APL, an improvement in APL uptake can potentially reduce the need for APL overload.…”

Section: Generation Of Protease-resistant Aplmentioning

confidence: 99%

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Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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Section: Generation Of Protease-resistant Aplsupporting

confidence: 77%

Section: Generation Of Protease-resistant Aplmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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“…Inhibition of antigen presentation by blocking a disease-specific MHC on antigen presenting cells with peptide (and occasionally non-peptide) ligands has been previously explored as a therapeutic strategy for autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type I diabetes, and experimental autoimmune encephalomyelitis (6)(7)(8)(9). Notwithstanding initial promise in animal models of these diseases, however, such therapeutic agents have failed to show clinical benefit (10,11).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

et al. 2006

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Human leukocyte antigen DQ2 is a class II major histocompatibility complex protein that plays a critical role in the pathogenesis of Celiac Sprue by binding to epitopes derived from dietary gluten and triggering the inflammatory response of disease-specific T cells. Inhibition of DQ2 mediated antigen presentation in the small intestinal mucosa of Celiac Sprue patients therefore represents a potentially attractive mode of therapy for this widespread but unmet medical need. Starting from a pro-inflammatory, proteolytically resistant, 33-residue peptide, LQLQPFPQPELPYPQPELPYPQPELPYPQPQPF, we embarked upon a systematic effort to dissect the relationships between peptide structure and DQ2 affinity, and to translate these insights into prototypical DQ2 blocking agents. Three structural determinants within the first 20 residues of this 33-mer peptide, including a PQPELPYPQ epitope, its N-terminal flanking sequence and a downstream Glu residue, were found to be important for DQ2 binding. Guided by the X-ray crystal structure of DQ2, the L11 and L18 residues in the truncated 20-mer analogue were replaced with sterically bulky groups so as to retain high DQ2 affinity but abrogate T cell recognition. A dimeric ligand, synthesized by regiospecific coupling of the 20-mer peptide with a bifunctional linker, was identified as an especially potent DQ2 binding agent. Two such ligands were able to attenuate the proliferation of disease-specific T cell lines in response to gluten antigens, and therefore represent prototypical examples of pharmacologically suitable DQ2 blocking agents for the potential treatment of Celiac Sprue.

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“…Selections of mimetic functionalities were based on molecular modeling. They discovered compounds with IC 50 s as low as 50 nM [72]. The same group reported designing, based on phage display and X-ray crystallographic data, peptide and peptide-mimetic HLA-DR ligands with significant binding affinity and robust activity inhibiting T-cell activation in vitro [79].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, HLA-DR4 is associated with autoimmune hepatitis [39] and HLA-DR2 with multiple sclerosis [38,49]. The key role of MHC proteins in modulating immune system activity make them attractive targets for therapeutic agents of autoimmune and inflammatory disorders [72][73][74][75].…”

Section: Introductionmentioning

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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Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

Cited by 53 publications

References 37 publications

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

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

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