ABSTRACT
A mimotope is an antibody-epitope-mimicking peptide retrieved from a phage display random peptide library. Immunization with antitumor antibody-derived mimotopes is promising for inducing antitumor immunity in hosts. In this study, we isolated linear and constrained mimotopes from HBJ127, a tumor-suppressing anti-CD98 heavy chain mAb, and determined their abilities for induction of antitumor activity equal to that of the parent antibody. We detected elevated levels of antipeptide responses, but failed to detect reactivity against native CD98-expressing HeLa cells in sera of immunized mice. Phage display panning and selection of mimotope-immunized mouse spleen-derived antibody Fab library showed that HeLa cell-reactive Fabs were successfully retrieved from the library. This finding indicates that native antigen-reactive Fab clones represented an undetectable minor population in mimotope-induced antibody repertoire. Functional and structural analysis of retrieved Fab clones revealed that they were almost identical to the parent antibody. From these results, we confirmed that mimotope immunization was promising for retrieving antitumor antibodies equivalent to the parent antibody, although the co-administration of adjuvant compounds such as T-cell epitope peptides and Toll-like receptor 4 agonist peptides is likely to be necessary for inducing stronger antitumor immunity than mimotope injection alone.
Subject(s)
Antibodies/immunology , Fusion Regulatory Protein-1/immunology , Neoplasms/immunology , Animals , Antibodies/isolation & purification , Antibodies, Neoplasm/genetics , Antibodies, Neoplasm/immunology , Epitopes/genetics , Epitopes/immunology , Fusion Regulatory Protein-1/genetics , HeLa Cells , Humans , Immunization , Mice , Neoplasms/genetics , Neoplasms/therapy , Peptide Library , Peptides/administration & dosage , Peptides/chemistry , Peptides/immunology , Toll-Like Receptor 4/metabolismABSTRACT
Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N(9)-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Subject(s)
Adenine/analogs & derivatives , Adenosine A2 Receptor Antagonists/pharmacology , Antiparkinson Agents/pharmacology , Antipsychotic Agents/pharmacology , Receptor, Adenosine A2A/chemistry , Vasodilator Agents/pharmacology , Adenine/chemical synthesis , Adenine/pharmacology , Adenosine A2 Receptor Antagonists/chemical synthesis , Animals , Antiparkinson Agents/chemical synthesis , Antipsychotic Agents/chemical synthesis , Catalepsy/chemically induced , Catalepsy/drug therapy , Humans , Male , Mice , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity Relationship , Vasodilation/drug effects , Vasodilator Agents/chemical synthesisABSTRACT
A new approach was developed for the synthesis of 4'-modified neplanocin A analogues, as potential inhibitors against S-adenosyl-L-homocysteine hydrolase. The vinylstannane 13, a key intermediate in the present approach, was prepared by radical-mediated sulfur-extrusive stannylation.
Subject(s)
Adenosine/analogs & derivatives , Adenosylhomocysteinase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Enzyme Inhibitors/chemistry , Sulfur/chemistryABSTRACT
A new approach was developed for the synthesis of 4'-modified neplanocin A, as potential inhibitors against S-adenosyl-L-homocysteine hydrolase. Vinylstannane derivative 5, a key intermediate in the present approach, was prepared by radical-mediated sulfur-extrusive stannylation.