Peptide scaffold

Fluorescently modified fibrils are a useful probe. Furthermore, MacPhee and Dobson have shown that it may be possible to bind other non-peptidic functional groups, provided they can be covalently linked during synthesis. They also demonstrate that utilizing intrinsic fibril structural features might be one approach to the production of peptide scaffolds with well-defined ligand spacings. 

Semino CE, Merok JR, Crane GG et al (2003) Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three- dimensional peptide scaffolds. Differentiation 71 262-270... 

Holmes TC, de Lacalle S, Su X et al (2000) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc Natl Acad Sci 97 6728-6733... 

Bifunctional adamantyl, as a hydrophobic central core, can be used to construct peptidic scaffolding [151], as shown in Fig. 27. This is the reason why adamantane is considered one of the best MBBs. This may be considered an effective and practical strategy to substitute different amino acids or DNA segments on the adamantane core (Fig. 28). In other words, one may exploit nucleic acid (DNA or RNA) sequences as linkers and DNA hybridization (DNA probe) to attach to these modules with an adamantane core. Thus a DNA-adamantane-amino acid nanostructure may be produced. 

Adamantane can be used to construct peptidic scaffolding and synthesis of artificial proteins. It has been introduced into different types of synthetic peptidic macrocycles, which are useful tools in peptide chemistry and stereochemistry studies and have many other applications as well. Introduction of amino acid-functionalized adamantane to the DNA nanostmctures might lead to construction of DNA-adamantane-amino acid nanostmctures with desirable stiffness and integrity. Diamondoids can be employed to constmct molecular rods, cages, and containers and also for utilization in different methods of self-assembly. In fact, through the development of self-assembly approaches and utilization of diamondoids in these processes, it would be possible to design and constmct novel nanostmctures for effective and specific carriers for each dmg. 

Vancomycin aglycone (VAG) contains the same peptide scaffold as vancomycin, but it lacks the disaccharide unit (C53H52CI2N8O17, molecular mass of 1142). The basic... 

Subramanian A, Ranganathan P, Diamond SL. Nuclear targeting peptide scaffolds for lipofection of nondividing mammalian cells. Nat Biotechnol 1999 17(9) 873-877. 

Baltzer and co-workers have utilized a synthetic peptide scaffold to incorporate features of transaminase enzymes [ 13]. Using this approach, they have attempted to achieve the selective and tight binding of a pyridoxal phosphate coenzyme observed in transaminase enzymes. A synthetic helix-turn-helix peptide known to dimerize into a four-helix bundle was chosen as the platform for design [5]. 

Work in the Imperiali laboratory has also focused on exploring the ability of minimal peptide scaffolds to augment the rate of coenzyme-mediated transaminations [22-25]. To accomplish this, a strategy has been developed in which the core functionality of the coenzyme is incorporated as an integral constituent of an unnatural coenzyme amino acid chimera construct. Thus, non-cova-lent binding of the coenzyme to the peptide or protein scaffold is unnecessary. Both the pyridoxal and pyridoxamine analogs have been synthesized in a form competent for Fmoc-based solid phase peptide synthesis (SPPS) (Fig. 7) [23,24]. 

One advantage of the coenzyme amino acid chimera approach is that it is compatible with solid phase peptide synthesis. Consequently, the reactive functionality can be readily and selectively delivered to any site in the peptide. Additionally, both natural and unnatural residues can be incorporated throughout the peptide scaffold, and related compounds can be investigated rapidly by combinatorial synthesis techniques. 

More recently, the Pam amino acid chimera has also been incorporated into a small j0j0a-motif peptide scaffold [28]. The family of BBA peptides was developed in our laboratory as structured platforms for the design of functional motifs. These motifs are attractive because they are small enough (23 residues) to be easily synthesized by standard solid phase synthesis methods. Additionally, the motifs appear to possess sufficient structural complexity to influence coenzyme properties while still being amenable to structural characterization by standard spectroscopic techniques [3, 29, 30]. The BBA peptides include a -hairpin domain with a type IT turn connected by a loop region to an a-heli-cal domain (Fig. 10). Packing of the sheet and helix against one another is accomplished by hydrophobic contacts created by a hydrophobic core of residues. 

Most recently, Baltzer and co-workers have incorporated a lysine-bound nicotinamide into a more complex peptide scaffold [75]. This approach takes advantage of the augmented reactivity of a lysine residue contained in a helix-turn-helix scaffold (as described previously [76]). An adjacent histidine is able to selectively catalyze the formation of an amide bond between activated esters and the lysine c-amino group under aqueous conditions. Thus, reaction of the 42-residue peptide LA-42 withp-nitrophenyl hT-methylnicotinate in an aqueous solution at pH 5.9 yields the nicotinoyl-functionalized peptide (Fig. 27). 

These minimalistic peptide scaffolds potentially provide a biologically relevant laboratory in which to explore the details of heme-peptide interactions and, with development, perhaps approach the observed range of natural heme protein fimction. These heme-peptide systems are more complex than typical small molecule bioinorganic porphyrin model compoimds, and yet are seemingly not as enigmatic as even the smallest natural heme proteins. Thus, in the continuum of heme protein model complexes these heme-peptide systems lie closer to, but certainly not at, the small molecule limit which allows for the effects of single amino acid changes to be directly elucidated. 

Scheme 9 Ugi-4CR + cyclization approaches to six-membered pseudo-peptidic scaffolds...

Figure 14.8 (Left) Primary sequence of peptide MAXI with /8-hairpin promoted intramolecular folding, leading to the reversible formation of self-assembled /8-sheets. (Right) Cryo-TEM image of self-assembled peptide scaffolds. Scale bar = 200 nm. Reprinted from Schneider et al. (2002). Copyright 2002 American Chemical Society.

Peptide scaffold- and nonpeptide template-based design strategies ... 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Specific examples of peptidomimetics which illustrate peptide scaffold- and nonpeptide template-directed drug-design strategies as applied to protease in-... 

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