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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
- Veröffentlichungsjahr: 2024
Naturally-derived biomaterials invite immense interest from diverse segments of science and engineering. Recent decades have witnessed a leap in knowledge and efforts in ongoing research with biomaterials as synthons, yet biomaterial research never fails to create surprises. This book summarizes modern knowledge of Bioderived Materials for beginners in research and advanced readers in materials science.
The book lays the foundations of understanding the design and development of mimetic peptides and enzyme mimetic bioinorganic catalysts, including the toolsets used in the process. Next, the book demonstrates different approaches for obtaining task-specific designer hydrogels. Additional topics covered in the book are tissue engineering and regenerative medicine. From this point, the book presents information on complex biomaterials systems: bacterial cellulose, cell membrane architecture for nanocomposite material design, and whole cellular microorganisms. Chapters provide applied knowledge with information on the strategies used to design novel biomaterials for applications such as drug delivery, therapy and controlled chemical synthesis.
In summary, this book brings together a wealth of information on Bioderived Materials with versatile applications, derived from different sources, such as plant derivatives and microorganisms (in part or whole as synthons), benefitting readers from multidisciplinary backgrounds.
Readership
Graduate students in materials science and biotechnology, industry professionals and early career researchers.
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FOREWORD
Biomaterials hold critical solutions to the myriad of problems modern societies face. Consequently, over the past several decades, biomaterials research has undergone a sea-change, attracting scientists and engineers from almost all conceivable backgrounds to investigate them from their perspectives. A biomaterial scientist today thus needs to be equipped with a multi-disciplinary understanding of the different aspects of any material under question and must have a general awareness of the various modifications being tried out on different types of materials. This edited book attempts to provide awareness to the students and researchers in this field of the fundamental concepts associated with the design and development of such building blocks and, subsequently, how such ideas can be used to manipulate different biomaterials to achieve the desired goals. The book chapters, contributed by the researchers, are arranged in order of complexity, starting with the fundamental concepts associated with the design and development of organic and inorganic materials, different polymers used as scaffolds for tissue engineering and complex systems like cell membranes and even whole organisms. I hope this edited book will be an asset for any student or researcher engaged in biomaterials research.
PREFACE
Naturally-derived biomaterials (Materials derived from different organisms including animals, plants and microorganisms) invite immense interest from diverse segments of science including chemistry, physics, materials sciences, bioengineering, chemical engineering, etc. Although the last few decades have witnessed a thriving effort towards understanding the ongoing research with biomaterials as synthons, yet biomaterial research never fails to create surprises.
This book was conceived with the idea to summarize the modern knowledge of this field as well as lay the foundation principles for researchers and engineers from different backgrounds interested in exploring new research avenues within biomaterial sciences. For instance, the first chapter helps to lay the foundations of peptide chemistry and presents the toolsets that can be used to address / overcome the challenges associated with the design and development of peptides and peptidomimetics with desired functionalities. Chapter 2 sheds light on how these toolsets can be utilized for designing natural enzyme mimetic bioinorganic catalysts with a specific focus on redox active enzymes. Subsequently, in Chapter 3, the authors thoroughly discuss the guiding principles for tailoring bioinspired scaffolds that promote hydrogel formation through the self-assembly of peptides/peptide-based amphiphiles. They present a conceptual demonstration of the different approaches that can be considered for the tailoring of task-specific designer hydrogels for diverse therapeutic applications. Alongside, such scaffolds are now being widely used in applications related to tissue engineering and regenerative medicine which is the topic covered in Chapter 4. Here the authors present strategies for employing different moieties to build human-relevant disease models for a few highly fatal non-communicable diseases like cardiomyopathy, cancer, neuropathy and others. Further progressing with such biomaterials, in Chapter-5 the authors discuss another class of biopolymer namely Bacterial cellulose (BC) which finds widespread applications in healthcare and other industries. Here they have summarized the additives and techniques used to modify BC to form nanocomposites for applications in different industrial sectors.
Moving further from simple to more complex systems, in Chapter 6, the authors present the architecture of the cell membranes, drawing attention to how nature uses its self-designed nano-composite materials to enable execution of desired reactions under given environmental conditions. From the complex cellular membrane system, an even more complicated system is discussed in Chapter 7, wherein the authors have presented strategies to use whole cellular microorganisms for designing novel drug delivery systems. It is expected that the microbe-based drug delivery systems would possess reduced toxicities or side effects and can surely serve as a futuristic advanced drug carrier to improve patients’ health.
In summary, this book focuses on bringing together diversified materials with versatile applications, derived from different sources, commencing from plant derivatives to microorganisms in partial or whole as synthons, under one roof such that readers from various disciplines end up having reasonable content.
List of Contributors
Peptidomimetics a Versatile Synthon for Biomaterials: Design Principles and Solutions
Ankita Sharma1,Naureen Khan1,Vaibhav Shivhare1,Rishabh Ahuja1,Anita Dutt Konar2,3,*Abstract
Bioorganic chemistry, an interdisciplinary scientific branch of chemistry and biology, has grabbed considerable impetus in the last few decades, owing to its important insights into the functioning of biological systems at the molecular level. Primarily it is a discipline of science that involves the study of biological processes mainly proteins and peptides at transcriptional, translational, or posttranslational levels. Yet, at the molecular level, our basic knowledge and understanding of the structure-activity relationship (SAR) of peptides/proteins remain in their infancy. Indeed, the dissection of multidomain proteins into small and simpler fragments, shed light on the design of scaffolds that seems to mimic the function of natural proteins in an efficient way, thereby giving rise to the birth of PEPTIDOMIMETICS. At times, the mimetics of critical functional protein domains, are advantageous over normal proteins/peptides in terms of specificity and therapeutic benefits. Henceforth the latter are considered to be expensive models for the investigation of molecular recognition. In this book chapter, our effort lies in modulating the basics of principles of peptide chemistry, challenges encountered, and some very efficient examples of how Peptidomimetics serves as a road map to resolve various stumbling blocks for PROTEOLYSIS and others.
1. INTRODUCTION
1.1. What are Peptides?
Peptides are condensed products/polymers of two or more amino acids that are interlinked together through amidation forming an amide bond also known as a peptide bond [1, 2]. The latter possesses a partial double bond character with a nearly trans configuration that restricts the rotation around this bond, thereby making it resistant to hydrolysis (Fig. 1.1) [1, 2]. Now in a peptide sequence, if the number of amino acid residues exceeds more than 50, it is coined as PROTEINS and if less, it is considered to be PEPTIDES.
Fig. (1.1)) In peptides A) Principle of amide bond formation; B) Double bond character.1.2. A Brief Overview of Different Amino Acids
Amino Acids are bricks of proteins that possess an amine and a carboxylate functionality. Most importantly it contains an R group (side chain) appended to the same carbon, commonly referred to as the α-carbon (Fig. 1.2). There are twenty different natural amino acids, which vary in the nature of R [1, 2]. The sidechains are classified on the basis of their nature into hydrophobic and hydrophilic residues as described below (Figs. 1.3-1.5). These synthons perform important roles not only in catalytic function but also in different processes of cell metabolism. The basic stereochemistry of L-amino acids has been presented in Fig. (1.6).
Fig. (1.2)) Architectural representation of an amino acid. Fig. (1.3)) The categories in which the amino acids are classified.2. BASIC PRINCIPLES OF PEPTIDE SYNTHESIS
2.1. Need for Protecting Groups
If in a substrate there is more than one reacting centre, the synthesis strategy of the target molecule (TM) becomes complicated, if the reagent reacts with equal efficiency to the other reacting sites. In such chemical reactions, the reactivity of other centers should be MASKED, with the assistance of simple groups whose introduction and removal are easy and user-friendly (Figs. 1.7, 1.8). Henceforth originates the necessity of PROTECTING GROUPS (PG) [3].
Fig. (1.4)) The 20 Different Amino Acids with variation in Sidechains. Fig. (1.5)) The structures of the two newly invented Amino Acids.The criteria for an effective protecting group are: a) The PG should not only be highly selective in functional group protection but its introduction and removal should also be easy and user-friendly. b) In both directions of the reaction, the yield should be quantitative. c) Generally introduction of PG increases the number of steps in a particular transformation. Therefore, the choice of the groups should be done in such a way, as to involve minimum steps, but obtaining the products in high yield.
2.2. For Peptide System
As mentioned in Figs. (1.1, 1.2), an amino acid contains two reacting centers, namely an amine and a carboxylate respectively. So, for a better understanding of the bond formation strategy, the synthesis of the dipeptide: Val-Leu has been considered.
Now both the amino acids Val and Leu contain one amine and carboxylate each. Therefore, there are four different reacting centers; a) Amine of Val; b) Carboxylate of Val; c) Amine of Leu; d) Carboxylate of Leu. So, when a coupling reaction needs to be carried out there are possibilities of the formation of four different products: a) Amine of Val with Carboxylate of Val: Val-Val; b) Amine of Leu with Carboxylate of Leu: Leu-Leu; c) Amine of Val with Carboxylate of Leu: Val-Leu; d) Amine of Leu with Carboxylate of Val: Leu-Val.
Fig. (1.6)) Basic Stereochemistry of an α-Amino acid and its Representation in different Projection formulae. Fig. (1.7)) Synthesis strategy of peptide coupling reactions.These dipeptides exhibit comparable polarity, henceforth are extremely tedious to separate through any chromatographic technique. Therefore, the desired molecule always remains as a mixture. In order to get rid of such complications, the assistance of the protecting groups seems important, such that the desired products could be easily separable and obtained in the purest form.
2.3. Problems Encountered in Peptide Reactions
In coupling reactions, the first step involves the activation of the carboxylates with suitable coupling reagents (Fig.1.9). This in turn is followed by a nucleophilic attack of the amine to the activated complex forming the desired product. Surprisingly, under the experimental coupling conditions (slightly basic pH), another phenomenon commonly known as racemisation, occurs owing to the ionization of the hydrogen tethered to the α-carbon. Additionally, there occur a few other side reactions, which often retard the reaction kinetics and gives rise to several byproducts. The major side reactions in peptide coupling reactions are the formation of A) N-Carboxyanhydride (Fig. 1.9), Diketopiperazine (Fig. 1.9b) and Guanidine (Fig. 1.9c) [4].
Fig. (1.8)) Different PGs for amino and carboxyl protections.Fig. (1.10) shows a typical representation of a peptide (here pentapeptide, Val-Ala- Phe-Ala-Ile), that is read, starting from the N-terminus, followed by the residues present in the sequence and ultimately reaching the C-terminus.
To get rid of such racemization issues, coupling reagents with appropriate suppressants are used, that not only reduce the racemization at the chiral center but also decrease the extent of side reactions. In addition, they also function as a rate enhancer (Fig. 1.10). Thus, the integrity of the chiral center is retained. Moreover, the choice of suitable Protection Groups for both N and C terminus, solvent systems, temperature, and pH maintenance often plays a crucial role in overcoming such challenges.
Fig. (1.9)) Probable by-products obtained under the experimental conditions of coupling reactions. Fig. (1.10)) Representation of a pentapeptide Val-Ala-Phe-Ala-Ile following the conventional approach. Fig. (1.11)) Various coupling reagents used for peptide synthesis to overcome the extent of racemization.The various non-covalent interactions that stabilize peptides have been enlisted in Figs. (1.11, 1.12). We tried to correlate the extremely powerful effect of weak interactions to the story of Gulliver Travels by Jonathan Swift. In the story, we learned that the small lilliputs were collectively capable of winning over the giant Gulliver and making him lie down. In a similar way, although the individual effect of weak correspondences is not strong enough, but their collective efforts lead to wonders……THE DEVELOPMENT OF MAGNIFICENT MATERIALS WITH ROBUST AND UNBELIEVABLE ACTIVITIES.
Fig. (1.12)) Various Factors stabilizing Peptide Assembly.3. STRUCTURAL ORGANIZATION IN PROTEINS
3.1. Primary (1°) Structure
From this part of the protein, we get a preliminary idea about the nature of amino acid residues constituting the backbone. It comprises two terminals, namely the amino or N and the carboxyl or C-termini respectively. Counting of the amino acids commences from the amino-terminus (NH2-group), which is devoid of the formation of any peptide linkages. The two methods of Edman degradation / tandem mass spectrometry permit us to investigate the one-to-one residue determination (Fig. 1.13) [2].
Fig. (1.13)) Hierarchical Nature of Protein Structural Organisation [10].3.2. Secondary (2°) Structure
The smaller folded substructures which are repeatedly present in a peptide sequence are commonly known as the secondary structure. In a particular solvent system, a peptide molecule does not remain in an extended conformation. Rather it adopts a folded one depending on the polarity of the side chains and the mutual rotation of the backbone. The twist of the backbone occurs in such a way that the entire motif gets stabilized utilizing weak non-covalent interactions (Fig. 1.13). Different secondary structures become interconnected with the help of a turn or a strip giving rise to a “super secondary structural unit” (Fig. 1.13) [2].
3.3. Tertiary (3°) Structure
Three-dimensional arrangement of atoms in a single polypeptide chain comprises the tertiary structure which is known to be the native domain, which might be monomeric or multimeric. A protein in actuality adopts a folded conformation. The secondary elements are stabilized by the native folds known as the active conformation which is mainly stabilized by weak noncovalent interactions like H-bonding, Electrostatic or Ionic, Hydrophobic and Van der Waals interactions. The origin of an amino acid in a protein can be correlated with the hydration energy of the individual amino acid, residue, side chain entropy, primary sequences and solvents [2]. It has been learned that the hydrophilic sidechains possess the likelihood of becoming solvated/shielded mainly by H-bonding and other weak forces like salt bridges and disulfide linkages. On the contrary, the hydrophobic sidechains get deeply buried forming the hydrophobic core, and stabilizing the globular proteins. But membrane proteins constitute both hydrophobic and hydrophilic distributions separately, unlike globular proteins Fig. (1.13) [1, 2].
3.4. Quaternary (4°) Structure
It is the overall three-dimensional arrangement of different polypeptide units, non-covalently linked with weak interactions generating large protein complexes, which serves as a single functional unit (multimer). If the complex comprises two subunits it may be recognized as dimers, if three and four then as trimers and tetramers respectively and so on. They are actually linked by symmetry operations. In case the subunits are identical, they are known as homomeric complexes, and if different, as heteromeric units. Enzymes are primarily complexes of proteins that display a wide range of activities. But for this, the symmetry, orientation of the complexes and stoichiometry of the composition play a vital role in displaying the activity (Fig. 1.13).
4. TOOLS FOR STABILIZING SECONDARY STRUCTURAL ORGANIZATION OF PROTEINS: INTRODUCTION TO TORSION ANGLES AND RAMACHANDRAN PLOT
Basically, for understanding the protein structure, adequate knowledge of torsion angle seems important [5]. They are angles between two different planes. We learned that the peptide bonds between different amino acids, (represented by ω) adopt a double bond character that restricts the rotation of other residues tethered to it (Fig. 1.1). This is because the torsion angle Cα-N-C′- Cα(ω) is prohibited to adopt an extended conformation with values nearly 180o or 0o. Generally, the trans conformation (ω ~ 180o) is preferred over syn (ω~ 0o) to avoid steric crowding of the bulky side chains of the particular amino acid residues (Fig. 1.14).
Fig. (1.14))Trans and Cis configurations of peptide bond (ω) [10].Unlike the peptide bond ω, there are two other single bonds namely N-Cα and Cα−C commonly depicted as C′-N-Cα−C′ (ϕ) and N- Cα− C′-N (ψ) (Fig. 1.14), that display many degrees of freedom of rotation. But the nature and angle of rotation are largely dependent on the sidechains attached (Fig. 1.14). For example, if in a peptide chain, one R is bulky Pro, the degree of rotation around the ϕ bond would be sterically hindered owing to the constrained cyclic structure of the amino acid (Fig. 1.14). On the other hand, if Pro is replaced by Gly, the ϕ bond becomes much more flexible. Thus, we find that the nature of rotation and subsequently the angle (with which that particular bond is represented) largely depends on R. Therefore, it is evident that the composition of amino acids largely determines the permissible angle of rotation for a protein to exhibit a particular secondary structure, maybe a helix or a sheet. Thus, if we are aware of the torsion angles and need to determine whether an unknown sequence would prefer a β−sheet or α−helix or some other, it would be very easy to obtain the conformation with the help of a contour diagram, known as the Ramachandran plot. The plot is basically a computer-aided tool of ϕ (along x-axis) verses ψ (along y – axis) with an angle ranging from -180 to +180 along both axis (Figs. 1.15, 1.16). According to Ramachandran and his co-workers, there are certain permissible regions specified in the map that are considered to be the regions specific to a particular secondary structure (Figs. 1.15, 1.16). This indicates that the diagram exhibits three small sterically allowed regions that produce different secondary structures [6-8]. The ϕ−ψ values for the various secondary structures are listed in Table 1.1. For instance, if a peptide sequence possesses highly positive values of ϕ and ψ, that particular sequence would prefer an α- helix structure. On the contrary, if ψ is high, with lower ϕ, a β-sheet would be preferred. To gain a deeper understanding of the nature of sheets, the exact values of the torsion angles need to be mapped in the Plot (Figs. 1.15, 1.16) [5]. Indeed, a basic idea of the torsion angles, allows us to identify the secondary structural features easily as the ϕ−ψ values for a particular amino acid residue remain fixed along the chain. The secondary structures are mainly stabilized by weak non-covalent interactions that confer stability to the entire protein unit.
Fig. (1.15)) Two linked peptide units and single headed arrows indicating the backbone torsions as ϕ, ψ and ω. The torsion angles for rotation about the amino acid side chains is designated as χ [10]. Fig. (1.16)) A detailed representation of Ramachandran map [10].The Ramachandran plot of some of the amino acid residues using both normal and relaxed Van der Waals interaction is represented in Fig. (1.17). As all proteinous amino acids except Glycine have a Cβ carbon atom, the Alanine map can be considered to be a prototype for allowed conformations for others.
Fig. (1.17)) The Ramachandran map for (a) Glycine (b) L-Alanine and (c) D-Alanine. The area enclosed within the solid line corresponds to the fully allowed region. The dotted line encloses the partially allowed region [10].5. DIFFERENT FOLDING PATTERNS/SECONDARY STRUCTURES OF PROTEINS
5.1. Helices
Helices are an important secondary architectural element observed in proteins (Fig. 1.18) [20]. They are classified into three categories based on various parameters 1) α-helix, 2) 310 helix, and 3) π-helix (Figs. 1.19, 1.20). Out of these categories, the α-helix and 310-helix are frequently observed in proteins whereas the π-helix occurrence is very rare. Detailed analysis of helix geometry has been reported in the literature [21-26]. Characteristic geometric parameters of different helices have been listed in Table 1.2 [21-26].
Fig. (1.18)) Different secondary structural features of proteins. Fig. (1.19)) Criteria for Helix classification. Fig. (1.20)) A perspective view of ideal (a) 310- (b) α- and (c) π helical structures. 4→1 hydrogen bonding in the 310 helix, 5→1 hydrogen bonding in the α-helix and 6→1 hydrogen bonding in the π helix are observed. The broken lines indicate hydrogen bonds [10].5.1.1. α-helix
This secondary structural motif of protein was discovered in the year 1951, by Linus Pauling [28]. After careful analysis of the crystallographic parameters of a variety of small molecules, he predicted that this conformation is the most stable one as observed in proteins. These structures have 3.6 residues per turn, a pitch of 5.4 Å, with 5→1 H- bonds between ith residue carbonyl with i+ 4th residue amine (Figs. 1.20, 1.21). It is located at the bottom left corner of the Ramachandran map. This conformation can adopt a right-handedness (ϕ, -57; ψ, -47) or a left-handedness (ϕ, 57; ψ, 47) depending upon the direction of rotation of the peptide backbone. The dipoles in the helix are oriented in such a way, that all the carbonyl groups project out of the helix plane, but point in the same direction. On the other hand, the NHs point in an opposite direction such that effective overlap occurs between the groups stabilizing the structures. Some important features of α-helices have been mentioned such as length distribution [33], conformation at the termini [34], geometry and bending [35], residue preferences at the termini [36-39], helix signals [40, 41], spatial preferences of ion pairs [42], water insertion [43], hydrophobic moments [44], amphipathicity in helices [45] and helix dipole [46-48].
Fig. (1.21)) Pictorial diagram of some basic features of α-helices.5.1.2. 310-helix
A 310-helix is an energetically unfavorable and rare element compared to α-helix in proteins [28-32]. It is characterized by 3.0 peptide units per turn with a ten-membered H- bond between the carbonyl group of ith residue with i + 3th amino functionality, being located at the edge of an allowed region in the Ramachandran map (Fig. 1.20). This is why 310-helix are occasionally observed in proteins, and in short fragments that are frequently distorted from ideal 310 conformations. However, this 310-helix is commonly observed in synthetic peptides with α-amino isobutyric acids (Aib) residues [49].
5.1.3. π-helix
Apart from the abundant α-helix and relatively less abundant 310-helix, extremely rare π-helices are also observed in proteins (Fig. 1.20). It is mainly characterized by 4.4 peptide units per turn with 6→1 hydrogen bonds and is wider and shorter than an α-helix [11-15]. A shorter stretch of π-helix has been found in Catalase [15].
5.2. β-sheets
After helix, the second major structural element that is ubiquitous (20-28%) in globular proteins is the β-strand. The β-strand possessesϕ, ψ angles of values nearby -120o, and 140o in the allowed zone of the Ramachandran plot. The extended nature of the polypeptide chain causes the positioning of the side chains of consecutive residues in opposite directions for effective non-covalent interactions to occur. Several such adjacent β-strands orient themselves in different ways giving rise to two different types of β- sheets as described Fig. (1.22) [16-19].
Fig. (1.22)) The H- bonding patterns in the β-pleated sheets. Side chains are omitted for clarity.The latter is stable in comparison to the former due to a more favourable orientation of the H- bonds and less dipole moment of the peptide bond. The peptide chain in a β- sheet is fully extended maintaining a distance of 0.35 nm between the neighbouring Cαatoms. β-sheets are slightly curved and sometimes assemble to form a β-barrel [35]. Analysis of various features of the β-strands so far includes the number of residues in a strand and no. of strands in a sheet [50, 51], preferences towards parallel and antiparallel association [52], preferences of residue “in register” in forming β-strands [53], salt bridge stabilization between residues at position i and i+ 2 [54, 55], bulges in β-strands, packing and higher ordered structures [56, 57].
5.3. Reverse Turns
Reverse turns are a special class of secondary structural elements of proteins that cause the reversal of the peptide backbone. They are categorized on the basis of the number of members of H- bonds formed (Fig. 1.23) [58-73].
Fig. (1.23)) Structures of different reverse turns involving L-amino acid residues. Only hydrogen bonded atoms are shown.5.3.1. β-Turn
β- Turns, the most important secondary structural elements of protein were first discovered in 1968 by Venkatachalam while he was performing molecular modelling studies [60]. They are known to stabilize tertiary structures in proteins, initiate protein folding and facilitate several intermolecular recognition [61-63].
Recently, it has been documented that β-turns function as subunits for the formation of extended β-sheets and subsequently amyloid-like fibrils, which serve as a prime route for many neurodegenerative diseases [61-63]. They are categorized mainly on the basis of backbone torsion angles and H-bonding patterns. In a typical β-turn, the presence of three amino acids is mandatory, where the ith residue carbonyl forms an intramolecular H-bond with the i+3th residue amino group as described in Fig. (1.23). There are three different types of turns namely I, II and III. Various types of β-turns observed in proteins are shown in (Fig. 1.24) along with the geometric parameters in Table 1.3 [60, 74-76].
Fig. (1.24)) Structures of different reverse turn involving L-amino acid residues. Only hydrogen-bonded atoms are shown [10].5.3.2. γ-Turns
Single amino acid chain inverters that can form 3→1 hydrogen bonds are known as γ-turns [77]. In comparison with the β-turn, γ-turns are rare elements of proteins. Depending upon the torsion angle, there are two types of γ-turn present in proteins, (a) inverse γ-turn and (b) classical γ-turn (Fig. 1.25), (Table 1.4) [78]. Inverse γ-turns are frequently found in proteins in contrast to classical γ-turns [79]. The characteristic parameters of different γ- turns are described.
Fig. (1.25)) Structures of (a) classical γ-turn and (b) inverse γ-turn with a 1←3 intramolecular hydrogen bond [10].6. β-TURN PEPTIDOMIMETIC
6.1. Peptidomimetics and Their Importance
Peptides are ubiquitous in nature. This is because they are formed from amino acids which are environmentally benign in nature. Most importantly they are built up using the guidelines of self-assembly employing weak non-covalent interactions. Literature documentation reveals that the design of PEPTIDOMIMETICS (PEPTIDE-LIKE BEHAVIOUR) has gained significant impetus in the last few decades for its versatile applications in physiological processes [80-82]. But major problems associated with naturally occurring peptides as drugs are weak absorptivity, bioavailability, and fast metabolism kinetics. This prompted scientists to modify the natural peptidyl sequence such that key elements essential for activity are preserved but substituting the unstable peptide bonds with robust features that could overcome the hurdles associated with natural processes in the physiological system. Although significant efforts in peptidomimetic chemistry have been dedicated to the development of peptide-based enzyme inhibitors and hormones, current research underpins the design of modified peptide analogs with pharmacologically useful properties that mimic protein structures along with the creation of advanced materials with magnificent applicabilities.
6.2. How Peptidomimetics Reduces Proteolysis and Increases Therapeutic Effects?
A well-known example of peptidomimetics is the different analogs of somatostatin, a growth hormone that is known to regulate the endocrine system by its interaction with the G protein. Literature documentation reveals that during its course of action, it inhibits the release of numerous secondary hormones that influence the growth of embryos, from the primary stage to adult [83, 84]. A deeper look into the structure reveals that this cyclic peptide hormone contains a β-turn conformation centered on the S-S disulfide bond of Cysteine which is held responsible for governing the growth activity. But sooner the Cys residue was replaced by a D-amino acid, keeping other residues unchanged, the modified hormone retained its activity. In search of designing more efficient β-turn mimetics, the constrained cyclic side chain of Pro, was substituted by N-Alkylated amino acids. This is because the side chain functionality in the latter is retained which is absolutely lost in the former circumstance [84-86]. Experimental evidence revealed that the N-Methylated Analogue exhibited similar activity to that of Somatostatin. But, in the N-methylated derivative as soon as the Phe residue was replaced by Tyr, the modified peptide displaced 100 times more potency than that of the original hormone (Fig. 1.26).
Another exciting example involves the design of a peptidomimetic scaffold of thyrotropin. This hormone is known to stimulate the thyroid gland to produce thyroxine (T4), and triiodothyronine (T3), which control the metabolism of the tissues in the body. But suffers from limited proteolytic stability. However, the replacement of the peptide bond with the cyclohexane scaffold, keeping the orientation of the pharmacophoric groups unchanged, resulted in enhanced beneficiary activities (Fig. 1.27) [33, 34]. Thus, the observations indicate the efficiency of the peptidomimetics over their peptide counterparts.
Fig. (1.26)) The structure of Somatostatin and some of the β-turn mimetics. Experiments reveal that mimetics exhibit better activities in comparison to normal hormones. Fig. (1.27)) The structure of Thyrotropin-releasing hormone and its Cyclohexane mimetic.Along this line, the group of Gennari, and Scolastico have developed bicyclic lactams 2.01 and 2.02 (Fig. 1.28) as turn mimics, which assisted in the formation of β-sheets when incorporated into peptides [87]. In this regard, the work from the group of Kelly needs special mention [88]. In another work, they used this moiety to develop β-sheet mimics (2.03). The recent contribution from the group of Soth and Nowick utilizing peptide/oligourea/azapeptide hybrid oligomer 2.04, as a hairpin mimic has attracted considerable attention [89]. A few years back Gellman and his group developed a nipecotic acid derivative which when incorporated into peptides (Fig. 1.29), resulted in the generation of a β-hairpin structure with remarkable activities [90].
Fig. (1.28)) The structure of some β-turn mimetics developed by Gennari, Scolastico, Kelly and Nowick et. al.Fig. (1.29)) Structures of some β-turn mimetics developed by Gellman and his group.Another strategy to stabilize β-turns is to use sugar amino acids (Saa) in the backbone (Fig. 1.30) [91, 92].
Fig. (1.30)) Some developed β−turn mimetics using sugar moiety.The replacement of the backbone amide bonds with isosteres represents another of the most widely used synthetic strategies to improve in vivo degradation. These modifications not only affect the chemical features of the peptide bond, but also the conformational profile which is reflected in their binding affinity [93]. The different amide bond isosteres used are presented in Fig. (1.31). For instance, the thioamide functionality obtained by replacing the carbonyl oxygen with the heteroatom sulfur (Fig. 1.31) induces increased polarity and rotational barrier around the peptide bond, conferring them as efficient protease inhibitors [94]. Alternatively, the carbonyl carbon atom could also be stop gaped by heteroatoms, like sulfur in the case of the sulfonamide (Fig. 1.31 II), or phosphorous in the phosphonamide (Fig. 1.31 III) or oxetane rings (Fig. 1.33 IV), which are known to display similar efficiency. Other commonly used isosteres are olefins, which are advantaged due to their ability to preserve the planarity of the peptide bond and the associated cis/trans isomerism (Fig. 1.31 V-VI) [95, 96]. Another approach that gained significant importance includes the locum of the alpha carbon with a nitrogen atom, generating the azapeptides (Fig. 1.31 VII
