Self-adjuvanting
vaccines, wherein an antigenic
peptide is covalently bound to an immunostimulating agent, have been
shown to be promising tools for immunotherapy. Synthetic Toll-like
receptor (TLR) ligands are ideal adjuvants for covalent linking to
peptides or proteins. We here introduce a conjugation-ready TLR4 ligand,
CRX-527, a potent powerful lipid A analogue, in the generation of
novel conjugate-vaccine modalities. Effective chemistry has been developed
for the synthesis of the conjugation-ready ligand as well as the connection
of it to the peptide antigen. Different linker systems and connection
modes to a model peptide were explored, and
in vitro
evaluation of the conjugates showed them to be powerful immune-activating
agents, significantly more effective than the separate components.
Mounting the CRX-527 ligand at the N-terminus of the model peptide
antigen delivered a vaccine modality that proved to be potent in activation
of dendritic cells, in facilitating antigen presentation, and in initiating
specific CD8
+
T-cell-mediated killing of antigen-loaded
target cells
in vivo
. Synthetic TLR4 ligands thus
show great promise in potentiating the conjugate vaccine platform
for application in cancer vaccination.
Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six‐membered nitrogen‐containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool‐based (internal asymmetric induction), (2) chiral auxiliary‐based (relayed asymmetric induction) and (3) asymmetric catalysis‐based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.
Cyclic peptides represent a popular class of macrocyclic drug candidates and therefore their solid phase synthesis has attracted much attention. In this contribution we present an efficient method of side‐chain anchoring for ornithine and lysine residues to be used in the standard Fmoc‐based synthesis of cyclic peptides via on‐resin cyclization. We demonstrate that the side chain of ornithine and lysine protected with N‐Boc‐group can efficiently be converted to the isocyanate which is then immobilized on Wang‐type resin in almost quantitative yield. We further show the synthesis of four biologically active cyclic peptides employing the side chain ornithine anchoring. Our method is at least on a par with the previously reported methodologies in terms of yield and the purity of the final products and is arguably operationally more straightforward.
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