CHEMICAL BIOLOGY

Peptidomimetics

Claudio Toniolo and Fernando Formaggio, Institute of Biomolecular Chemistry, Padova Unit, CNR, Department of Chemistry, University of Padova, Padova, Italy

doi: 10.1002/9780470048672.wecb439

This review article provides an introduction to folded and extended conformational motifs of synthetic peptidomimetics as templates for chemical biology applications. Several variants of these 3-dimensional structures have been assessed, which comprise versatile scaffolds for presentation of side-chain and main-chain peptide groups for molecular recognition. Specifically, relevant parameters and stereochemical consequences are discussed for helices of peptidomimetics based on: 1) α-amino acids alkylated (e.g., methylated or ethylated) at the C^α-atom; 2) α,β-didehydroamino acids, in particular α,β-didehydrophenylalanine, with a carbon-carbon double bond between the α- and β-positions; 3) N-alkylated α-amino acids, whereby the side chains typical of coded residues are transferred from the C^α- to the N-atom; 4) β-amino acids, the subclass of residues investigated most extensively in which the amino and carboxyl functionalities are separated by more than one carbon atom; and 5) short-range, backbone-to-backbone cyclizations that generate small-ring, monolactam or dilactam building blocks.

Introduction

Peptidomimetic is a molecule that bears identifiable resemblance to a peptide that, as a ligand of a biologic receptor, can imitate or inhibit the effect of a natural peptide. Numerous peptidomimetics have been developed over the past 25 years by bioorganic and medicinal chemists. Some molecules (i.e., those with modifications in the backbone amide group) also have been termed pseudopeptides or peptide bond surrogates (1). These synthetic analogs of peptides have a variety of applications, but most expanded interest in this area focuses on their potential for developing metabolically stabilized and/or more potent and selective bioactive compounds. The complex synthetic aspects (2) and relevant biological data (1, 3, 4) of peptidomimetics have been summarized extensively in review articles and in book chapters. In this introductory review, we focus on the 3-dimensional (3-D) structural properties of peptidomimetics characterized heavily by a few, well-studied amino acids with modifications in the main chain and/or in the side chain. An effort was made through appropriate citations to expose the nonexpert and the beginning graduate students to the remarkable advances made in this area of research. The field of peptidomimetic chemistry is entering new decades of exploding activity. This time is exciting as new techniques and methodologies have now made it possible to answer questions that were not possible to address even few years ago. Many developments ushered in the new era of peptidomimetic chemistry, which include advancements in solution and in solid-phase peptide synthesis, organic synthesis, nuclear magnetic resonance and related biophysical techniques, and mass spectrometry. These advancements take advantage of an increasing understanding of protein folding. Numerous examples now exist of low molecular weight peptides and peptidomimetics that adopt folded or extended structures, and in some cases they serve as exceptional substitutes for their much larger protein counterparts in life processes. Chemists in both academia and industry are making important strides to push the frontiers in these areas. With the ability to incorporate unnatural amino acids that have strong conformational or nucleating bias, it will be possible to force much smaller peptides and peptidomimetics to adopt appropriate 3-D structures and functions. The future for the young scientists who ultimately want to pursue this line of research is indeed very promising. Rather than looking at peptidomimetics as a mature field, it should be argued that we are only in our infancy in terms of sophistication. Every reason exists to believe that a combination of approaches, which include biophysical and functional characterizations, will propel this area forward in the next years. It is especially important for those who are considering future research areas to analyze seriously the potential of such studies.

Among the various types of known ordered secondary structures adopted by peptides formed exclusively by α-amino acid building blocks, in this review article we shall discuss the classic α-helix, the 3₁₀-helix, the 2.0₅-helix, and the type-I poly(Pro)_n helix. Relevant parameters for these helices are given in Table 1.

Table 1. Relevant average parameters for peptide helices based on L-configurated α-amino acids discussed in this review article

*In the poly(Pro)_n I helix, all ω(C_i^a-C'_i-N_i+1-C_i+1^a) torsion angles are in the unusual cis conformation (0°).

¹The (C'_i-1-N_i-C^a_i-C'_i) torsion angle.

²The (N_i-C^a_i-C'_i-N_i+1) torsion angle.

³Number of amino acids per helical turn (positive values refer to right-handed helices, whereas negative values refer to left-handed helices)

⁴Axial translation (per residue).

⁵Pitch or axial translation per helical turn.

Peptides Based on C^a-Alkylated α-Amino Acids

Peptides rich in the noncoded C^a-methylated α-amino acids (1) are biased strongly to fold tightly into the intramolecularly H-bonded, α-helical, or the strictly related 3₁₀-helical conformation (5-9), the latter generated by sequences of helical β-turns (10, 11). The same 3-D structural propensities are shared by the C^a,a-cyclized α-amino acids (2).

By inserting appropriate amino acid side chains (e.g., hydrophilic and hydrophobic), it is feasible to construct amphiphilic helices (with two faces that possess different properties). The conformational strategy should take into account the parameters typical of each of the two helices, in particular that: 1) The α-helix (Fig. 1a) is characterized by a fractional number of amino acids per turn (3.5) and consequently its smallest repeat (i.e., the shortest main-chain length that brings two side chains exactly one on top of the other) is a heptad (7 residues); and 2) in the 3₁₀-helix (Fig. 1b), which has an integer number of amino acids per turn (≅3.0), a triplet of residues selected carefully will produce the expected amphiphilicity.

The amphiphilic helical structure of most antibacterial peptides is a prerequisite for their propensity to form channels across the double-layered biological membranes (12). In aqueous solution, positions a and d of the α-helical heptad repeat (a, b, c, d, e, f, g) (13) require hydrophobic residues for the onset of the widespread antiparallel dimer (or multimer) superstructure (α-helix coiled coil) (14-16) (Fig. 2). The hydrophilic positions e and g, immediately on the back, reinforce the dimer stability via ionic interactions. Deep knowledge of the factors operative in helix dimer formation may help our understanding greatly of protein-protein interactions in chemical biology.

The preferred conformation of peptides based heavily on C^a-ethylated α-amino acids (3) is different. In the resulting 2.0₅-helical conformation, intramolecular H-bonding takes place between the N-H and C=O groups of the same amino acid building block (17, 18). To achieve the pentagonal disposition, the H-bonding parameters are distorted remarkably and the sp³ N-C^a-C' bond angle is compressed severely (by ≅6.5°). An example of this fully extended (all-traws) conformation, based on C^a,a-diethylglycine (3, R=CH₂-CH₃) (17), is illustrated in Fig. 3. This twofold structure is extremely rare in globular proteins and is known only for a Gly-rich sequence (19).

Only few C^a-alkylated a-amino acids occur naturally (in peptide antibiotics) (20, 21), which include Aib (α-aminoisobutyric acid or C^a,a-dimethylglycine) (1, R=CH₃), Iva (isovaline or C^a-ethyl, C^a-methylglycine) (1, R=CH₂-CH₃), and (αEt)Nva (C^a-ethylnorvaline) (3, R=(CH₂)₂-CH₃).

Figure 1. Right-handed (a) α-helical and (b) 3₁₀-helical peptide models from L-configurated, C^a-methylated a-amino acids viewed along the helix axis, highlighting their amphiphilic properties. In these models, the largest black (oxygen) and white (nitrogen) atoms on the right side are those of the hydrophilic side chains of Ser, Asp, Glu, and Lys.

Figure 2. Antiparallel dimer formation generated by an amphiphilic α-helix.

Figure 3. The X-ray diffraction structure of the 2.0₅-helical homo-pentapeptide from C^a,a-diethylglycine with five, consecutive C=O∙∙∙H-N intramolecular H-bonds (17).

Peptides Based on C^a,β-Didehydro α-Amino Acids

C^a,β-Didehydro α-amino acids (∆AAs) are found in a variety of naturally occurring microbial and fungal metabolites, in a limited number of globular proteins, and in polycyclic peptide antibiotics (22). Bioactive peptide molecules that contain these residues are less prone to enzymatic degradation.

The double bond between the sp² C^a and C^β atoms of ∆AAs induces higher lipophilicity and geometric alterations in the bond distances and angles and restricts the conformational flexibilitites of the peptide backbone and the side chain as compared with those of protein residues. Most 3-D structural studies in this subclass of peptidomimetics have exploited ∆Phe mainly because of its convenient chemical synthesis and interesting conformational properties. ∆Phe exists in two diastereomeric forms: the Z-configurational isomer (∆^ZPhe, 4), where the N-H group is in the cis disposition with respect to the benzyl moiety, and the E-isomer (∆^EPhe, 5), where it is in the trans disposition. Almost all conformational studies described so far have been performed on the Z-isomer (22-24) essentially because a large part of the synthetic routes results in this stereoisomer.

From the investigations on ∆Phe-based peptides, it is clear that the 3-D disposition largely preferred by this residue is the helical conformation (23, 24). Therefore, most corner positions of the various types of β-turns and all positions of 3₁₀-/α-helices are accessible easily to this residue. Fig. (4) shows the right-handed 3₁₀-helix generated by a double repetition of the model triplet -(∆^ZPhe-∆^ZPhe-L-Ala)-. Aromatic amino acid residues, which include ∆^ZPhe (25), are known to play a significant role in the stability of the helixcoiled coil motifs. The importance of weak interactions that involve aromatic moieties in molecular recognition and in the de novo design of miniproteins has been highlighted frequently.

Another useful property of ∆Phe is its strong absorption in the near-UV region (≅280 nm). This characteristic has been exploited in several studies to probe peptide conformational transitions and helix screw sense changes of chiral switches (26-28).

Interestingly, a series of homo-peptides derived from the C^a,β-didehydro α-amino acid with the shortest side chain (C^a,β-didehydroalanine or ∆Ala, 6) was shown unambiguously to overwhelmingly adopt a multiple, consecutive, fully extended conformation (29). These peptide molecules are essentially flat, including the amino acid side chains, and form completely planar sheets (Fig. 5). This uncommon peptide 3-D structure is stabilized by two types of intramolecular H-bonds, N_i-H∙∙∙O_i=C_i (typical of the 2.05-helix) and C^β_i+1-H∙∙∙O_i=C_i (characteristic of ∆Ala peptides). The molecules are isolated and pack in layers without any significant contribution from intermolecular N-H∙∙∙O=C H-bonds. For this exceptionally flat (”sole-like”) peptide structure, it is reasonable to foresee a bright future as a potentially active bridge in charge transfer systems.

Figure 4. Right-handed 3₁₀-helical conformation formed by a double repetition of the -(∆^ZPhe-∆^ZPhe-L-Ala)- model peptide: views orthogonal to (a) and down (b) the helix axis.

Figure 5. The variant of the 2.0₅ helical conformation adopted by the homo-tripeptide from C^a,β-didehydroalanine (29).

Peptides Based on N-Substituted α-Amino Acids (Peptoids)

In 1992, Simon et al. (30) introduced a new concept in the search for potentially bioactive peptide molecules: The side chain on the α-amino acid a-carbon is shifted by one atom along the backbone to the next nitrogen to generate a peptoid (7) (i.e., an N-substituted oligoglycine). Peptoids have been shown to be protease resistant (only tertiary amide groups are present in the main chain), oral bioavailable, and easy to synthesize in oligomeric forms with complex sequences (31). Peptoids have been also exploited for the construction of many biologically active compounds in many different fields of pharmaceutical research.

Because of this principal structural divergence from coded peptides, peptoids lack amide protons. This property precludes the formation of the intramolecular H-bonds that contribute largely to the stabilization of the most common helical structures of α-peptides. Unlike that of α-peptides, the peptoid backbone is inherently achiral (as it is based on Gly residues). However, it has been reported that sufficient bias to form stable helices of a specific screw sense can be provided by side chains with an α-chiral carbon atom (that is linked directly to nitrogen) (32, 33). The extraordinary resistance of these helices to loss of their ordered secondary structure is another intriguing property of peptoid molecules.

The only published X-ray diffraction structure for any peptoid oligomer, the Nrch (8) homo-pentamer, shows clearly that the molecule is folded in a left-handed helical conformation with all tertiary amide bonds in the cis conformation (33). The periodicity of this helix is approximately three residues per turn, with a pitch (axial translation per turn) of about 6.7 A. The C=O groups are aligned with the helix axis. The handedness of the peptoid helix is controlled by the chirality of the N-side chain enantiomer. The values of the φ, ψ backbone torsion angles for each residue indicate a semi -extended conformation [i.e., close to the classical type-I poly(Pro)_n helix] (Fig. 6).

Figure 6. Molecular representation of the left-handed peptoid helix with the φ, ψ, ω backbone torsion angles typical of type-I poly(L-Pro)_n.

Peptoid helices are detected in structure-supporting solvents even in relatively short oligomers. Because intramolecular C=O∙∙∙H-N H-bond formation cannot be the driving force for peptoid secondary structure, the steric influence of the bulky and chiral side chain is likely to provide the required constraint. Interactions between side-chain groups, and between side chains and the carbonyls of the main-chain amides, may add stability to the ordered secondary structure. However, for very short oligomers (34) or peptoids based on N-substituted a-amino acids with a small side chain (35), such as Nala (also termed sarcosine, Sar, 9), complex mixtures of conformers associated with either cis or trans tertiary amide groups have been detected. In addition to the classic CD technique, the contribution of other spectroscopies, such as pulsed ESR (36), may be of value for the 3-D structural validation of peptoid molecules.

Peptoid nanostructures will be useful for investigating principles of macromolecule self-assembly and for fabricating novel functional architectures in biotic systems.

Peptides Based on β-Amino Acids

ω-Amino acids (that have more than one carbon atom intervening between the amino and carboxyl functions) possess a larger degree of conformational variability than a-amino acids. Initial conformational investigations of oligomers of to-amino acids were driven by the extensive interest in the various forms of nylons. More recently, a large body of 3-D structural investigations on β-amino acid oligomers have been discovered, but the conformational preferences of peptides based on γ- and δ-amino acids and of “hybrid” peptides (e.g., those formed by α- and β- or α- and γ-amino acids) are also the subject of numerous spectroscopic and X-ray diffraction analyses (37-39). In this section, we summarize the most relevant conformational results extracted from the studies of peptides rich in the β-amino acids listed below.

In β-Ala (10), the simplest amino acid of this class, the central, characteristic C²-C³ bond is unconstrained and can adopt values for the related θ (also called |x in some publications) torsion angle of approximately ±60° (gauche) and 180° (trans). Detailed analyses of the rotational flexibility about this bond in linear β-Ala peptides revealed that θ is mostly trans oriented (40, 41). Also, these studies provided almost exclusive evidence for the formation of extended peptide chains, which usually self-aggregate into sheet-like structures.

More recently, introduction of (one or multiple) substituents and chiralities on the C² and C³ atoms (11-13, 15, 16), and incorporation of C²↔C³ (14), N↔C² (17), and N↔C³ (18) cyclized motifs seemed to facilitate folding of P-peptides into a new type of helices (42-47). A variety of these ordered structures has been authenticated. If the nomenclature is used that terms peptide helices according to the number of atoms involved in the pseudocyclic structure generated by the intramolecular C=O∙∙∙H-N H-bond, those found most frequently are the 14-, 12-, and 12/10-helices. Interestingly, although the direction of the H-bond for the 12-helix is the same as that typical of α-peptides (i.e., from a C-terminal N-H group to an N-terminal C=O group; in this specific case i ← i + 3), the direction is reversed (i → i + 1 and i → i + 2, respectively) for the 10- and 14-helices. β-Amino acids in the extended conformation may also produce parallel or antiparallel pleated-sheet structures.

The 14-helix emerged as the best documented structure among the β-peptide folded structures. The φ, ψ torsion angles are extended (±130 — 140°). The 0 value is constrained (e.g., by the cyclohexyl ring of the cyclic β^2,3AA) (14) (n = 2), close to 60°. Both the pitch and the diameter of this ternary helix are ≅5.0 A.

When the substituents on the C² and C³ atoms of the β-amino acid are part of a five-membered ring (as in the trans cyclic β^2,3 AA, 14, with n = 1), the accessible θ torsion angle is restricted to about ±95°. The resulting 12-helix has a set of φ, ψ torsion angles near 90°. The helix repeats approximately every 2.5 residues, with a pitch of ≅5.5 A, and a diameter slightly less than 4.0 A.

The 12/10-helix was found in alternating β²-(11) and β³-(12) monosubstituted residues. The dipeptide unit that contains a -CONH-bond with no adjacent R²/R³ substituents generates the 12-membered ring, whereas that with the two adjacent substituents is part of the 10-membered ring. This ordered structure consists of consecutive narrower 10-membered and wider 12-membered H-bonded rings. Consequently, the two successive H-bonded rings exhibit opposite directionality. In this conformationally mixed helix, the peptide planes of the 10-atom rings are approximately perpendicular to the helix axis, whereas the peptide planes of the 12-atom rings are aligned nearly with the helix axis. As in the 14-helix, the 0 value is close to ±60^°. The number of amino acids per turn is 2.7. The overall helix macrodipole is much smaller compared with those of the other helical structures. The C=O (and the N-H) bonds show an alternating up/down direction with respect to the helix axis.

Two (parallel and perpendicular to the helix axis) views for each of the three β-peptide helices discussed in this section are presented in Fig. 7. Recent applications of β-peptide helices to relevant biological issues (antibacterial activity, transport across cell membranes) (48-51) will certainly stimulate additional work in this promising area.

Figure 7. Two orthogonal representations for each of the β-peptide 14-, 12-, and 12/10-helices (a, b, and c, respectively) formed by a β² AA or/and a β³ AA, where R²/R³ are methyl goups. The H-atoms, except the -CONH- H-atoms, are omitted for clarity.

Lactam-Based Peptides

Several review articles and books have dealt extensively with the synthetic problems encountered and have discussed in detail the biological data of lactam-based peptides. However, insufficient attention has been paid to the conformational implications induced in the resulting constrained analogs (52-56). Here, we will mention briefly only those lactam-based conformational restrictions in peptides that are achieved by short-range cyclizations that involve the backbone N and C^a atoms (from residue i to residue i or i + 1). Therefore, conformational restrictions that involve the C' (carbonyl) atom and those obtained by medium- and long-range cyclizations, although of great theoretic and practical interest, have not been considered. In addition, in all peptides discussed in this section, the repeating N-C^a-C' sequence is maintained.

As a part of a program that evaluates N-acylated γ-lactams as conformationally constrained building blocks of pseudopeptide foldamers, homo-oligomers of L-pyroglutamic acid (L-pGlu) (19) to the tetramer level were synthesized (57). The preferred conformation of this pseudopeptide series with N_i ↔ C_i^a ring restriction in structure-supporting solvents was assessed by various spectroscopic techniques. In addition, the crystal-state structure of the N^a-protected dimer was established by X-ray diffraction. A high-level DFT computational modeling was also performed based on the crystallographic parameters. In this analysis, it was demonstrated that an αC-H∙∙∙O=C intramolecular H-bond is responsible for the stabilization of the s-trans -L-pGlu-L-pGlu- conformation by 1.4 kcal mol^-1. This effect can be detected easily by ¹H NMR because of the anomalous chemical shifts of the αCH protons present in all oligomers. In summary, a new polyimide-based, foldameric structure (Fig. 8) was developed that, if functionalized appropriately, holds promise as a rigid scaffold for novel functions and applications.

Figure 8. Computer model of the ternary helical structure of the pseudopeptide -(L-pGlu)₄-segment generated by the repeating ψ₁, ω₁, and ψ₂ backbone torsion angles obtained from the X-ray diffraction structure of Boc-(L-pGlu)₂-OH (Boc, tert-butyloxycarbonyl) (57).

The lactam restriction of peptide conformation (20) (C_i^a ↔ N_i+1) was proposed first by Freidinger et al. (58) with the aim at forcing the peptide bond (ω_i) to be trans and placing a severe constraint on the ψ_i torsion angle. Conformational energy calculations for (S)-3-amino-2-pyrrolidone (γ-lactam) and (S)-3-amino-2-piperidone (δ-lactam) derivatives indicate that the most stable conformations have ψ₁ values restricted to the range -125 ± 10°. As a consequence, these chiral mono-lactams can be accommodated readily at the left corner of a type II’ β-turn (φ = 60°, ψ = -120°) (10, 11), a position occupied typically by a-amino acids of R(D) chirality, but obviously not at the same position of a type-II β-turn (φ = -60°, ψ = 120°). X-ray diffraction, ¹H NMR, CD, and computer graphics analyses on a variety of analogs of bioactive peptides are in excellent agreement with the theoretic findings, in particular that underlie the strict requirement of reversing the chirality of the residue at the left-corner of the β-turn to keep the same type (II or II’) of chain folding when a 5(or 6)-membered ring lactam replacement is involved (59). Despite the gross conformational similarities between the 5- and 6-membered ring lactams, distinct biological properties usually are noted for peptides that contain such rings. More subtle differences in conformation and/or in bulkiness between the two lactams might be responsible for the observed diverging biological activities.

The effect of the incorporation of a succinimide (21) moiety into a peptide chain (another type of C_i^a ↔ N_i+1 ring restriction) has been examined carefully (60, 61). The five-membered succinimide annular system is an intermediate in the repair of selective degradations of side-chain deamidated proteins. It has been shown both theoretically and experimentally that L-Asu-Xxx- (Asu, α-aminosuccinyl) dipeptide sequences strongly favor the type-II’ β-turn, a behavior similar to that of the γ-lactam modification discussed above.

The conformational preference of the terminally blocked homo-trimer from (2S, 4R)-4-amino-5-oxopyrrolidine-2-carboxylic acid (22a), characterized by C_i^a ↔ C^a_i+1 ring restriction and an unique, alternating cis-trans secondary amide sequence was analyzed by X-ray diffraction (62). Using computer modeling, it was also shown that the rigid 3-D structure of the trimer can be exploited as a template to construct novel linear oligopeptide foldamers and large-ring cyclic correlates with self-recognizing properties (for the latter, see Fig. 9).

Figure 9. Computer models of: (a) the cyclic correlate based on 12 monomeric units of (2S,4R)-4-amino-5-oxopyrrolidine-2-carboxylic acid. The idealized backbone φ, ψ torsion angles are 120°, 120°, respectively. (b) The nanotubular structure resulting from vertical self-assembling of the cyclic correlate through intermolecular N-H∙∙∙O = C H-bonds that involve the trans amides (62). The black and white atoms are oxygens and hydrogens, respectively.

The most stable conformation of peptides that contain 3-amino-2-piperidone-6-carboxylic acid (22b), also an amino acid with a C_i^a ↔ C^a_i+1 ring restriction, has been determined by ¹H NMR (63). A chair conformation is a feature that characterizes the piperidone ring, Also, an intramolecularly H-bonded β-turn form is the most plausible explanation for the experimental finding on these peptides.

The synthesis of a novel macrocyclic (10-membered ring) dilactam (23, n = 2), an additional template with a C_i^a ↔ C^a_i+1 ring restriction that may promote formation of type-II β-turns, has been reported (64). By analysis of the ¹H NMR spectrum, it was established that a chair-like conformation is preferred for this ring structure and that the two amide groups are trans with roughly parallel planes. It seems, however, that the presence of the two macrocyclic secondary amide functions perpendicular to the plane of the turn would facilitate intermolecular association that leads to poor solubility and gel formation. A similar (11-membered) ring structure has been synthesized to generate a relatively rigid model of the bioactive peptide thymopentin. Peptides that contain two consecutive macrocyclic dilactams, separated by a C^a-C'-N-C^a region that retains flexibility about the ψ_i+1 and ψ_i+2 torsion angles, have been prepared (65). This swivel-like effect can allow the peptides to adopt low-energy folded conformations. From potential energy calculations, it was established that the best candidates for β-turn models are the 12-membered ring structures that have the configurational sequence L,L,D,D (in these compounds all amide groups are nearly trans planar). The 10- and 11-membered dilactams were shown to be higher in energy. The results of a CD-¹H NMR study are consistent with the presence of a β-turn in the —L-Lys-L-Glu-D-Lys-D-Glu-Ms-dilactam-bridged tetrapeptide.

In search for enkephalinamides with improved analgesic activity, conformationally restricted analogs, where the Tyr, Gly, Phe, and Leu/Met residues are cyclized to form a piperazin-2-one (24) (an N_i ↔ N_i+1 ring restriction), have been prepared. Analogs with either D-Tyr¹ or L-Leu⁵(L-Met⁵) are active. The absolute configuration of the piperazin-2-one derived from the intermediate dipeptide amide H-L-Phe-L-Leu-NH₂ has been assessed by X-ray diffraction. The enantioface-differentiating abilities of cyclic peptides that contain N,N’-ethylene-bridged dipeptides have been examined. The X-ray diffraction structure of an L-Ala-L-Ala piperazin-2-one derivative has been described (66). The ψ_i torsion angle is fixed at about —35°, whereas ф_i and ω_i, in part external to the ring structure, are trans.

Summary

In this introductory review we have presented the most relevant 3-D structural characteristics of a selected set of peptidomimetics that, hopefully, will be of help to the nonspecialized scientists for potential use in the currently exploding field of chemical biology. More specifically, we have discussed examples of peptide surrogates with main-chain and side-chain modifications either at the α-nitrogen or at the α-carbon, or at both α- and β-carbons, or with different types of cyclizations (N↔N, N↔C^a, and C^a↔C^a). For journal issues or books devoted to these and other types of peptidomimetics, the reader is referred to References 67-73.

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Further Reading

Bayley PD. An Introduction to Peptide Chemistry. 1990. Wiley, Chicester, U.K.

Benoiton NL. Chemistry of Peptide Synthesis. 2005. CRC Press, Boca Raton, FL.

Bodanszky M. Peptide Chemistry: A Practical Textbook. 1988. Springer Verlag, New York.

Gorske BC, Jewell GA, Guerard EJ, Blackwell HE. Expedient synthesis and design strategies for new peptoid construction. Org. Lett. 2005; 7:1521-1524.

Grant G. Synthetic Peptides: A User’s Guide. 2002. Oxford University Press, Oxford.

Gutte B. Peptides: Synthesis, Structures, and Applications. 1995. Academic Press, San Diego, CA.

Howl J. Peptide Synthesis and Applications, Vol. 298. Methods in Molecular Biology. 2005. Humana Press, Totowa, NJ.

Humphrey JM, Chamberlin AR. Chemical synthesis of natural product peptides: coupling methods for the incorporation of noncoded amino acids into peptides. Chem. Rev. 1997; 97:2243-2266.

Jones J. The Chemical Synthesis of Peptides. 1991. Clarendon Press, Oxford.

Noda K, Shimohigashi Y, Izumiya N. α,β-Dehydroamino acids and peptides, Vol. 5. The Peptides: Analysis, Synthesis, Biology. Gross E, Meienhofer J, eds. 1983. Academic Press, New York. pp. 285-339.

Shin SBY, Yoo B, Todaro LJ, Kirshenbaum K. Cyclic peptoids. J. Am. Chem. Soc. 2007; 129:3218-3225.

Zuckermann RN. Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 1992; 114:10646-10647.

Zuckermann RN. The chemical synthesis of peptidomimetics. Curr. Opin. Struct. Biol. 1993; 3:580-584.

See Also

Amino Acids, Chemistry of

Natural and Unnatural Amino Acids, Synthesis of

Peptide Synthesis

Peptides, Chemistry of

Synthetic Peptides to Define Structure-Function Relationships