ABSTRACT
BACKGROUND: p-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated 10BPA or borocaptate sodium (10BSH). METHODS: (1) IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-10B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice. RESULTS: Intravenous injection of IF7C conjugates of either 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7-10B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes. CONCLUSIONS: We conclude that IF7 serves as an efficient 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.
Subject(s)
Annexin A1/metabolism , Boron Compounds/administration & dosage , Boron Neutron Capture Therapy/methods , Neovascularization, Pathologic/radiotherapy , Peptide Fragments/metabolism , Phenylalanine/analogs & derivatives , Urinary Bladder Neoplasms/radiotherapy , Animals , Apoptosis , Boron Compounds/chemistry , Boron Compounds/metabolism , Cell Proliferation , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Nude , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Phenylalanine/administration & dosage , Phenylalanine/chemistry , Phenylalanine/metabolism , Tumor Cells, Cultured , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
An isopeptide of amyloid ß peptide 1-42 (isoAß42) was considered as a non-aggregative precursor molecule for the highly aggregative Aß42. It has been applied to biological studies after several pretreatments. Here we report that isoAß42 is monomeric with a random coil structure at 40 µM without any pretreatment. But we also found that isoAß42 retains a slight aggregative nature, which is significantly weaker than that of the native Aß42.
Subject(s)
Amyloid beta-Peptides/chemistry , Peptide Fragments/chemistry , Protein ConformationABSTRACT
The O-acyl isopeptide method was developed for the efficient preparation of difficult sequence-containing peptide. Furthermore, development of the O-acyl isodipeptide unit for Fmoc chemistry simplified its synthetic procedure by solid-phase peptide synthesis. Here, we report a novel isodipeptide unit for Boc chemistry, and the unit was successfully applied to the synthesis of amyloid ß peptide. Combination of Boc chemistry and the isodipeptide unit would be an effective method for the synthesis of many difficult peptides. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
Subject(s)
Amyloid beta-Peptides/chemical synthesis , Amyloid beta-Peptides/isolation & purification , Peptide Fragments/chemical synthesis , Peptide Fragments/isolation & purification , Solid-Phase Synthesis Techniques/methods , Amyloid beta-Peptides/chemistry , Humans , Islet Amyloid Polypeptide/chemical synthesis , Islet Amyloid Polypeptide/chemistry , Islet Amyloid Polypeptide/isolation & purification , Peptide Fragments/chemistry , Protein Structure, SecondaryABSTRACT
We attached 2-aminoethylamino groups to allophenylnorstatine-containing plasmepsin (Plm) inhibitors and investigated SAR of the methyl or ethyl substitutions on the amino groups. Unexpectedly, compounds 22 (KNI-10743) and 25 (KNI-10742) exhibited extremely potent Plm II inhibitory activities (K(i)<0.1 nM). Moreover, among our peptidomimetic Plm inhibitors, we identified the compounds with the highest antimalarial activity using a SYBR Green I-based fluorescence assay.
Subject(s)
Antimalarials/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylenediamines/chemistry , Protease Inhibitors/chemistry , Protozoan Proteins/antagonists & inhibitors , Thiazoles/chemistry , Antimalarials/pharmacology , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Computer Simulation , Ethylenediamines/chemical synthesis , Ethylenediamines/pharmacology , Phenylbutyrates/chemistry , Protease Inhibitors/pharmacology , Protozoan Proteins/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is known to be involved in the production of amyloid beta-peptide in Alzheimer's disease and is a major target for current drug design. We previously reported substrate-based peptidomimetics, KMI-compounds as potent BACE1 inhibitors. In this study, we designed and synthesized tetrapeptides as low molecular-sized inhibitors. These exhibited high potency against recombinant BACE1, with the highest IC(50) value of 34.6 nM from KMI-927.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Oligopeptides/metabolism , Amyloid beta-Peptides/metabolism , Drug Design , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Molecular Structure , Oligopeptides/chemistry , Oligopeptides/geneticsABSTRACT
Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.
