title: Novel complementary peptides to target molecules.
abstract: We generated an evolutionary computer program that generates complementary peptide (C-pep) sequences, with the potential to interact with a target peptide, by comparing several physico-chemical parameters of each pair of the complementary peptides being analyzed. We generated C-peps to target several molecules. About 30% of synthesized C-peps interfered with the function of their targets. C5a stimulates generation of TNFα and other inflammatory cytokines. Inhibition of C5a should be effective against sepsis, which impairs the status of cancer-bearing patients. One of the inhibitory C-peps of C5a, termed AcPepA, was effective in Cynomolgus monkeys intravenously infused with a lethal dose of bacterial LPS (4 mg/kg) destined to die. The monkeys were rescued by intravenous administration of 2 mg/kg/h of AcPepA. The excellent therapeutic effect of AcPepA is likely to be due to restriction of high mobility group box 1 (HMGB1) surge induced by the effect of C5a on C5L2, which is the second C5a receptor, since the released HMGB1 has the capacity to stimulate TLR4 as an endogeneous ligand resulting in further activation of inflammatory cells to release inflammatory cytokines forming a positive feedback circuit of inflammation.
authors.affiliation: Research Institute for Protein Science, Nakayama-cho 2-18, Mizuho-ku, Nagoya 467-0803, Japan. hiokada@med.nagoya-cu.ac.jp
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.forename: Alan
authors.initials: A
authors.lastname: Okada
authors.forename: Toyohiro
authors.initials: T
authors.lastname: Tada
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizue
authors.forename: Keiji
authors.initials: K
authors.lastname: Terao
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015936:Complement C5a / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000378:metabolism; D019020:Directed Molecular Evolution; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D025461:Feedback, Physiological; D024243:HMGB1 Protein / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000473:pathology; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044087:Receptor, Anaphylatoxin C5a / Q000502:physiology; D012984:Software; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D019151:Peptide Library; D010455:Peptides; D044087:Receptor, Anaphylatoxin C5a; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a