Peptide dendrimer

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

An interesting case in the perspective of artificial enzymes for enantioselective synthesis is the recently described peptide dendrimer aldolases [36]. These dendrimers utilize the enamine type I aldolase mechanism, which is found in natural aldolases [37] and antibodies [21].These aldolase dendrimers, for example, L2Dl,have multiple N-terminal proline residues as found in catalytic aldolase peptides [38], and display catalytic activity in aqueous medium under conditions where the small molecule catalysts are inactive (Figure 3.8). As most enzyme models, these dendrimers remain very far from natural enzymes in terms ofboth activity and selectivity, and at present should only be considered in the perspective of fundamental studies. 

Figure 3.8 Aldol reaction and peptide dendrimer catalyst.

Other types of branched peptide dendrimers, known as multiple antigen peptides (MAPs), have been synthesized to mimic proteins for applications, for instance as synthetic vaccines, serodiagnostics, peptide inhibitors and intracellular delivery vehicles. Since this concept has been recently described in detail elsewhere [11], only the conceptual framework will be briefly presented here. Tam and coworkers have developed a dendritic core based on lysine units for the construction of MAPs [12-15] (Fig. 3). Carrying antigens at their periphery these MAPs have been designed to increase antigenicity and immunogenicity of peptides. 

Monaghan, Sean, Griffith-Johnson, David, Matthews, Ian and Bradley, Mark (2001). Solid-phase synthesis of peptide-dendrimer conjugates for an investigation of integrin binding. Arkivoc, 2001, (Part (x)), 46-53. http //eprints.soton.ac.uk/19576/... 

Darbre T, Reymond J-L. Peptide dendrimers as artificial enzymes, receptors, and drug-delivery agents. Acc Chem Res 2006 39 925-934. 

Peptide dendrimers and related structures are covered in Section 14.1. They represent an important extension of peptide synthesis into novel structures.[13,14] Following the definition of dendrimers and the scope of their applications, strategies for the design and synthesis are described (Section 14.1.2). The routes include syntheses in solution (Section... 

Scheme 23 Synthesis of Cyclic Peptide Dendrimers through Sulfide Linkage 131 ...

The multivalency of peptide dendrimers has also been used to increase the binding avidity of antigens to antibodies in various immunological assays and diagnostic tests. 27,43,47,48,55-59 Examples in the literature have been reported where the MAP format increases the binding avidity and sensitivity, in some cases >100000 fold. In addition to immunology, MAP types of dendrimers have found applications in areas such as inhibitors, 44,45,51,60,61 artificial proteins, 62 affinity purification, 63 and intracellular transportation, 41 as well as in drug discovery. 53 ... 

The most common functional templates are those of simple amino compounds 4, amino acids 5, and dipeptides 8 (Scheme 3). The simplest amino templates, the tris(ethylene amine) ammonia types 6, 7, and 9 first used in organic dendrimers, have only just begun to be applied in forming peptide dendrimers. Constrained and usual amino acids and heterocyclic compounds such as porphyrin 13, have also been reported.1691... 

Most divergent syntheses of peptide dendrimers have been performed on the K2K type of core. For preparing homomeric peptide dendrimers, di-protected Lys such as Boc-Lys(Boc) or Fmoc-Lys(Fmoc) has been used to diverge the core for subsequent elongation of the... 

Chloroacetyl K2K and related dendrons are popular and convenient to prepare because of their reactivity with thiol moieties placed on peptide dendrimers for convergent syntheses.1P3 90 91 Furthermore, these dendrons are stable to acidic cleavage by either TFA or HF. The synthesis of a chloroacetyl K2K dendron 20c by Boc chemistry is illustrated in Scheme 8. 

The synthesis of peptide dendrimers covers a broad range of chemistry, from conventional schemes of peptide synthesis, to formation of amide bonds in organic solvents, to protein chemistry that includes conjugation, ligation, and semi-synthesis to form regiospecific amide or non-amide bonds in aqueous solutions. 

Goodman and co-workers177-3 have approached the divergent synthesis differently. In their syntheses of collagen models consisting of three copies of homomeric peptide chains, solid-phase schemes begin with monomers 44 and then the template, the Kemp tricarboxylic acid (KTA) 10,[80 is used to link three monomers, also on resin, to form the peptide dendrimers 46 via 45 (Scheme 12). 

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