Bioactive epitope

Stable plant peptides as carriers for bioactive epitopes 280... 

For the cycloscan, conformational libraries are synthesized by cyclization of continuous or noncontinuous bioactive epitopes and not by their insertion into a scaffold. Originally, the concept of cycloscan was introduced for the generation of backbone-cyclized peptide libraries 467 however, cycloscan can also be applied to other modes of cyclization. In this approach all components of each sublibrary bear the identical sequence, and differ from each other in distinct parameters that affect their conformation, but do not alter their connectivity, and hence their potential bioactivity. This is achieved by gradually introducing discrete conformational perturbations, which allow an efficient screening of the conformational space of the parent peptide. The majority of the components of such libraries should be inactive, because they do not overlap the bioactive conformation. However, the peptide that does fit the bioactive conformation should be very potent and have all the pharmacological advantages of cyclic peptides. 

Fig. 4 Self-assembling hydrogelators based on p-sheets. (a) Representative chemical structure of a peptide amphiphile, here without charged residues and with a heparin binding domain, (b) Peptide amphiphile with bioactive epitopes left) and its assembly leading to formation of ID fibers right). Reprinted from [136], Copyright 2010, with permission from Elsevier, (c) Graph showing the enhanced functional recovery for animals treated with the peptide amphiphile, as assessed via the BBB score. Adapted with permission from [78]. Copyright 2008 Society for...

Because the conditions for final protecting-group removal can be harsh, eliminating this step allows for the synthesis of materials containing sensitive bioactive epitopes. Consequently, the ability to synthesize substituted polymers utilizing both defined initiators and unprotected monomers constituted a critical advance in the synthesis of bioactive substituted polymeric displays via ROMP. Methods that have been used successfully for the incorporation of polar bioactive ligands are highlighted. 

Figure 8 Strategies for synthesizing block copolymere displaying bioactive epitopes, (a) Sequential polymerization of monomers bearing a bioactive epitope, (b) PPM of two orthogonally reactive blocks.

Figure 9 End-labeling strategies for the incorporation of bioactive epitopes, (a) Termination of the polymerization can be effected with aldehydes (molybdenum alkylidenes) or vinyl ethers (ruthenium carbenes) to install a single reporter group, (b) Termination of ruthenium carbenes with a vinyl carbonate or vinyl lactone leaves a terminal aldehyde or carboxylic acid that can be further derivatized. (c) Sacrificial synthesis An acetal orthioacetal block can be unmasked to reveal a single terminal alcohol or thiol that can be modified selectively.

IKVAV-containing PA-nanofiber scaffold induced very rapid differentiation of neural progenitor cells into neurons based on the amplification of bioactive epitope presentation to cells by the nanofibers (roughly estimated to be 7.1 X IQi IKVAV epitopes/cm2) [35],... 

The introduction of retro-, retro-inverso-, and PMRI-peptides with free and blocked C-and N-termini has been successful in numerous biological systems such as neurotransmitters, inhibitors of proteases and protein kinases, sweeteners, antimicrobial peptides, hormones, adhesion molecules, antigenic epitopes, immuno-modulators, and immunological probes. Table 1 provides an exhaustive list of retro-, retro-inverso-, PMRI-, and end-group-modified re/ro-mvmo-pseudopeptides derived from bioactive peptides. 

Fig. 4 Functional decoration (F) of self-assembled nanofibers to mimic fibrillar structures of the ECM. The monodisperse nature of the building blocks and the precise assembly motifs lead to nanostructures with well-defined functional surfaces. Adjusting of these faces enables the generation of bioactivity by presenting biorelevant epitopes [88, 92, 105, 108, 116, 128]...

Chimeric peptides are unnatural constructs consisting of bioactive compounds from at least two different peptide(s) and/or protein(s) or two sequences from different parts of the same protein. Such multifunctional peptide combinations are prepared to enhance the biological activity or selectivity of their components. New biological effects can also be achieved with the chimera. In this chapter the synthesis of three different types of chimeric peptides will be described. In a linear chimera, two peptide epitopes from different parts of glycoprotein D (gD) of herpes simplex virus (HSV) are combined. A branched chimera, built from linear peptides, consists of tuftsin oligomers with immunostimulatory activity and an epitope peptide of HSV gD. The third compound is a cyclic chimeric molecule, where a-cono-toxin GI as a host peptide is modified by the incorporation of a core epitope from HSV gD as a guest sequence. 

The Protein and Bioactive Peptide Sequences (BIOPEP) is a public database (Dziuba et al., 1999) containing 707 proteins, 2123 bioactive peptides, 65 allergenic proteins with their epitopes, and 224 sensory peptides and amino acids. Databases include information such as sequence, number of amino acid residues, molecular weight, activity, and references. BIOPEP can be browsed online and the user can search for a specific sequence. 

To end up with a predictive pharmacophore model, it is necessary to start with reliable structural and biological data. First of all, it is important to have correct 3D structures of all compounds under study. Thus, atomic valences, bond orders, protonation state and stereochemistry have to be checked carefully. Also the consideration of different possible tautomers is necessary when the bioactive form is not exactly known. Another prerequisite is the existence of a similar binding mode of all ligands under study. Experimental data, from competition experiments or protein-ligand crystal structures, can clearly point out that the ligands interact with the same binding epitope in a similar way and not on distinct binding sites. 

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