title: A cyclic peptide accelerates the loading of peptide antigens in major histocompatibility complex class II molecules.
abstract: Major histocompatibility complex (MHC)-loading enhancers (MLE) have recently attracted attention because of their ability to enhance the efficacy of peptide immunotherapeutics. As small molecular weight compounds, they influence the loading of peptides in MHC molecules by converting them from a non-receptive to a receptive state. Herein, we report a 14-mer cyclic peptide 1 (CP-1) as a new class of MLE-peptide. This peptide was used to investigate its loading on human leukocyte antigen (HLA)-DR molecules. It was found that CP-1 strongly accelerates peptide-loading on both soluble and cell surface HLA-DR molecules in a dose-dependent manner. The effect was evident for all subsets of HLA-DR tested, including HLA-DRB1*1501, indicating that it acts independently of P1-pocket size, which is the canonical MLE-binding site. Importantly, increased peptide-loading by CP-1 was correlated with improved CD4(+) T cell responses in vitro, while propidium iodide staining indicated low peptide-induced cytotoxicity. Thus, this study revealed a new class of peptide-based enhancers that catalyze peptide-loading by allosteric interactions with MHC molecules. Because of its low cellular cytotoxicity and high MLE activity, it may be useful in stimulating antigen-specific T cell responses for therapeutic purposes.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Saifullah
authors.initials: S
authors.lastname: Afridi
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Farzana
authors.initials: F
authors.lastname: Shaheen
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Olaf
authors.initials: O
authors.lastname: Roetzschke
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Zafar Ali
authors.initials: ZA
authors.lastname: Shah
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Syed Comail
authors.initials: SC
authors.lastname: Abbas
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Rizwana
authors.initials: R
authors.lastname: Siraj
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: makhmoor@iccs.edu.
authors.forename: Talat
authors.initials: T
authors.lastname: Makhmoor
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D041681:NIH 3T3 Cells; D010456:Peptides, Cyclic / Q000737:chemistry / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; D010456:Peptides, Cyclic
keywords: CD4(+) T cell responses; Cyclic peptide; HLA-DR1*0101; MHC class II molecules; MHC-loading enhancer