James P. Tam

Recent advances in multiple antigen peptides

The goals for the development of multiple antigen peptides (MAP) are to provide a rational and unambiguous system to multimerize different types of synthetic peptide antigens and to attach immunomodulating molecules for targeting and delivery. These goals have been largely realized and new designs of MAPs now permit a broad range of immune responses including CTLs and mucosal IgAs. Furthermore, significant advances by the inventiveness of many laboratories have led to applications of MAPs for serodiagnostic and other biochemical uses including those for drug discovery. An important aspect to accomplish various goals of MAPs is chemistry. New methodologies using unprotected peptides as building blocks have been developed to accommodate new and sophisticated design of MAPs. This review is written based on the personal perspective of my laboratory and will focus on the recent progress in MAPs, together with the chemistry to achieve their synthesis.

Acyl disulfide-mediated intramolecular acylation for orthogonal coupling between unprotected peptide segments. Mechanism and application

A highly efficient orthogonal coupling approach for peptide bond formation using unprotected peptide segments was described. The key element of this approach consisted of capturing an Npys modified N-Cys side-chain thiol of the amino segment with a Cα-thiocarboxylic acid of the acyl segment to form an acyl disulfide which undergoes rapid intramolecular acylation to generate an amide bond. A final product with a native Cys residue at the ligation site was obtained after a thiolytic reduction step.

12 – Synthesis and Applications of Branched Peptides in Immunological Methods and Vaccines

This chapter elucidates the synthesis and applications of branched peptides in immunological methods and vaccines. Branched peptides, such as multiple antigen peptides (MAPs), are artificial proteins that are significant in biochemical and biomedical applications. This chapter describes the methods for preparing MAPs and applications such as synthetic vaccines, serodiagnostics, and peptide inhibitors. It describes a new design of MAPs containing lipidated built-in adjuvant, which can be delivered by oral administration to elicit systemic and mucosal immunoglobulins as well as cytotoxic T-lymphocytes. It also describes orthogonal approaches by thiol and carbonyl chemistries to facilitate synthesis using unprotected peptide segments as building blocks and ligating them to the core matrix. Proteins as a class of biopolymers have the unusual capacity of displaying a diverse variety of folds and forms predetermined by the primary sequences and correlated to protein functions. Many of the functional sites are located on the surfaces, and some are continuous sequences consisting of 4–21 residues. This holds for the antigenic sites of proteins, which are referred to as epitopes. Other sites include those for attachment, recognition, location, and cellular compartment translocations and are known as motifs.

The MAP System

Conventional vaccines consisting of either killed or attenuated infectious agents are limited in their potential by several factors. These include hazards associated with the production, storage that requires a cold chain, presence of contaminating materials, risk of infection in immunocompromised people, and unwanted side effects in the case of incomplete attenuation of the pathogen.

Assembly of cyclic peptide dendrimers from unprotected linear building blocks in aqueous solution

Sequential weak base–aldehyde condensations are used to cyclise unprotected linear peptide fragments and then to assemble the cyclic products onto a dendrimeric antigen presenting molecule.