Peptide structural mimics

EMPl, selected by phage display from random peptide libraries, demonstrates that a dimer of a 20-residue peptide can mimic the function of a monomeric 166-residue protein. In contrast to the minimized Z domain, this selected peptide shares neither the sequence nor the structure of the natural hormone. Thus, there can be a number of ways to solve a molecular recognition problem, and combinatorial methods such as phage display allow us to sort through a multitude of structural scaffolds to discover novel solutions. 

Figure 5 Structures of phenylzine 15, tranylcypromine 16, and the peptide substrate mimics 17-19.

The benzene ring has been proposed as an isosteric replacement in a dipeptide to enforce either the tram l1 1 or the cis conformation 312>31 (Scheme 1). Similarly, 2-(amino-methyl)pyrrole-l-acetic acid (8, R = H) has been proposed as a cis peptide bond mimic,141 having the same number of atoms between the amino and carboxylic acid functions as in a dipeptide. Several other amino- and carboxy-substituted aromatic structures have been used as spacers in peptides 2-, 3-, and 4-aminobenzoic acids (Abz, e.g., 7), 2-, 3-, and 4-(amino-methyl)benzoic acids (Amb, e.g., 2), 2-, 3-, and 4-(aminophenyl)acetic acids (APha, e.g., 5), 2- (4), 3-, and 4-(aminomethylphenyl)acetic acid (Ampa), (aminomethyl)pyrrole-, -thiophene-, and -furancarboxylic acids 6, (aminomethyl)pyrrole- 8 and -thienylacetic acids, and aminobiphenylcarboxylic acids. 

Two important examples of cyclic peptides will be highlighted in which amino acid sequences of larger proteins have been successfully used as part of macrocyclic peptide structures to mimic in an almost pars pro toto approach important properties of the parent protein. 

Kishore R. P-Ala containing peptides potentials in design and construction of bioactive peptide and protein secondary structure mimics. Curr. Protein Pept. Sci. 2004 5 435-455. 

The realization that a non-peptide natural product was mimickingthe action of a natural peptide effector led Farmer to postulate that other non-peptide structures might be found that would mimic other peptide effectors (7). His concept of peptide mimetic," which later was called "peptidomimetic," proposed that... 

Structural and functional studies of a synthetic peptide that mimics a proposed membrane inserting segment of a Bacillus thuringiensis delta-endotoxin have been conducted. An NMR study of a methanol solution of a synthetic 31-mer peptide corresponding to the sequence of a putative pore-forming segment of the CrylA(c) toxin showed that the peptide exists as an a-helix. Hie peptide forms discrete, characterizable channels in planar lipid bilayers. It is possible that this helix is a component of the transmembrane pore formed by Bacillus thuringiensis delta-endotoxins in vivo. 

In addition to their many structural studies on )8- and y-peptides, Seebach and coworkers showed that human receptors accept )8-peptides that mimic natural a-peptides [65]. They modeled a cyclic )8-tetrapeptide placing phenylalanine, tryptophan, lysine, and threonine-like side chains in key positions designed to mimic a cyclic a-octapeptide derived from somatostatin (Fig. 36). 

Sheh et al. (206) used X-ray crystallographic studies to design potential compounds to block the polymerization of deoxyhemoglobin S (HbS). The / 6 mutation that occurs in this protein allows one molecule (the donor) to insert itself into a hydrophobic cavity of a second molecule (the acceptor) (Figure 20). Sheh and co-workers have designed a set of cyclic peptides that mimic the loop of the donor protein which inserts into the acceptor HbS. The structure of the cyclic peptides was suggested by modeling to be such that the conformation of the peptide is close to that required by the protein loop. 

It is a common practice to utilize chemically synthesized transmembrane peptides instead of intractable whole membrane proteins, as a first step, to understand their folding behavior, partial 3D structure, and the consequences in relation to their biological significance. Justification of such an approach is in many instances not always straightforward, unless the subsequent results are comparable with those of the whole intact protein system. Fortunately, the present 13C NMR results available from 13C-labeled intact bR can serve as a very convenient reference system to examine how effectively a model approach utilizing chemically synthesized transmembrane peptides can mimic the intact system, and meaningful conclusions can be drawn. 

Polyamino acids can be considered as models for conformational studies, providing an atomistic description of the secondary structural motifs typically found in proteins [30-39]. Two-dimensional hydrogen-bonded layers and columns in the structures of crystalline amino acids can mimic S-sheets and helices in proteins and amyloids [40 5], and can be compared with two-dimensional crystalline layers at interfaces [46-58]. Nano-porous structures of small peptides can mimic cavities in proteins [24, 59-63]. One can also prepare crystals in which selected functional groups and side chains are located with respect to each other in the same way, as at recognition sites of substrate-receptor complexes, and use the systems to simulate the mutual adaptation of components of the complex responsible for recognition. 

---