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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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StatPearls [Internet].

Biochemistry, peptide.

Jessica Forbes ; Karthik Krishnamurthy .


Last Update: August 28, 2023 .

  • Introduction

Peptides play an essential role in fundamental physiological processes and are necessary for many biochemical processes. A peptide is a short string of 2 to 50 amino acids, formed by a condensation reaction, joining together through a covalent bond. [1]  Sequential covalent bonds with additional amino acids yield a peptide chain and the building block of proteins.

Peptides are named based on the number of amino acid residues in the sequence. As peptide chains form between joining of the primary structure of amino acids, they may enlarge to become an oligopeptide when there are between 10 to 20 amino acids in the chain. In vivo, each amino acid is added to the amino-terminal of one amino acid to form a peptide chain. [1]  When there are greater than 20 amino acids, the peptide is an unbranched chain deemed a polypeptide.

Each amino acid comprising a peptide is called a “residue” since that is the portion remaining after the loss of water in the dehydration reaction. Amino acids are the organic starting molecule composed of a carboxyl-terminal and an amino group that makes up the foundation of a protein. Peptide synthesis depends on three main reactions: 1. an amino acid goes through a deprotection step, a preparatory reaction that adds the next amino acid to the chain, and lastly, a coupling reaction that forms the final peptide with functionality. [1]  In the second step, the amino acid becomes activated with several reagents. Thes carboxylic acid in the amino acid will react to make the activated form, which will then enter into a coupling reaction. After one round of peptide synthesis, this process is repeatable to add more amino acids until creating the desired length of the peptide.

Peptide bonds are resistant to conditions that denature proteins, such as elevated temperatures and high concentration of urea. Amino acids all have the same general structure, with a positive charge on nitrogen and negative on the carbonyl group. [1]

  • Fundamentals

Peptide bonds 

The peptide bond formed in the active site of the ribosome has a partial double-bond character. [2]  This bond is more rigid and planar than a single bond since double bonds are shorter and stronger and require more free energy to break them. Due to the steric interference of R groups, the bond is almost always a trans bond. [2]  The nature of the bond prevents complete free rotation between the carbonyl carbon and the nitrogen of the peptide bond. However, the bonds between the other carbon atoms can freely rotate. This configuration and allows for multiple configurations and isomers of peptides to be created. 

Bioactive Peptides

As amino acids combine to form a peptide, specific bioactive peptides can be designed with implications to the pharmaceutical industry and biologics design usage for therapeutic biomedical research. [3]  Extensive research has shown the multi-faceted role of bioactive peptides has demonstrated effectiveness in blood pressure decreasing, anti-microbial properties, anti-inflammatory, anti-thrombotic, improved response to infection, and anti-oxidant. [4]  The fundamental nature of peptides as the building blocks of proteins, allow for the synthetic and in vitro mimicking of these endogenous substances to that regulate specific cellular functions and facilitate an innumerable amount of biochemical process in the body. 

  • Cellular Level

The process of biochemical synthesis of a peptide from its primary amino acid primary structure to a final protein structure is a fundamental biological process. This section will provide an overview of the mechanisms involved in synthesizing a peptide sequence and highlight key cellular locations and specific enzymes. 

Biologically active peptides, including neurotransmitters and hormones and, are created from and RNA template, transcribed from DNA. [1]  First, a ribosome translates a signal sequence that docks it to a signal recognition particle (SRP) on the rough endoplasmic reticulum (RER). In vivo, after transiting from the nucleus to the cytoplasm to the attachment of a ribosome, mRNA will begin the process of translation and peptide chain formation.

The steps of translation subdivide into initiation, elongation, and termination. [1]  The initiation step includes an mRNA binding to a small ribosome subunit. [2]  A group of similar nucleotide sequences, termed Kozak sequences surround the start codon; they act as a landmark for small ribosomal subunit to recognize and attach the start codon, AUG, coding for Methionine, binds to the anticodon of tRNA. The large subunit holds an A, P, and E site, and the first step is the binding of the small subunit in the P site. [5]  After each amino acid attaches to its corresponding tRNA with the help of ATP, the enzyme aminoacyl-tRNA synthetase catalyzes the bond. [5]  As each peptide bond forms, linking together two amino acids, a condensation reaction occurs with the loss of a water molecule. [1]  

With expansion and addition of additional amino acids, a polypeptide is then created and destined to become the major macromolecule constituent of cells, protein. Post-translationally modification of peptides such as methylation, phosphorylation, acetylation can also alter the rates of peptide synthesis. [6]  

As a growing peptide forms, it is then cleaved from its signal sequence, forming a large preprohormone, which is then cleaved further into a prohormone. As a prohormone, it is packaged into vesicles and sent to the Golgi apparatus for further processing and to be proteolytically cleaved into their final form. The final peptide is packaged into secretory vesicles and sent into the cytoplasm and then leave the cell via exocytosis when they receive a stimulus.  

The established method in a laboratory setting for the production of the synthetic peptide is known as solid-phase peptide synthesis (SPPS). [7]  This process allows the rapid assembly of a peptide chain through a process of consecutive reactions of amino acid derivatives in a series of coupling, deprotecting techniques. [7] [8]

  • Molecular Level

Peptide Hormones 

Peptide hormones are water-soluble molecules that can range from 3 to 200 amino acids in lengths and shape and are linked by peptide bonds.  Peptide hormones are synthesized locally and can travel to remote tissues with an implication for physiological growth and differentiation. The paracrine and perhaps autocrine actions of these peptide hormones contribute to the growth, survival, and functionality of the tissues on which they act. [9]  These hormones range broadly in size, structure, and function. The following is only a concise list and does not represent all of the physiologic and endogenous peptide hormones in the body; however, these peptide families are of note.

Pro-opiomelanocortin (POMC) gene family  is originally a 241 amino acid residue that is cleaved at different lysine residues through proteolysis to create unique, active peptides. The peptides created include melanocyte-stimulating factor (MSH), adrenocorticotropic releasing hormone (ACTH), B-lipotropin, and B-endorphin, and are expressed in peripheral tissues and the brain. [10]

Oxytocin and ADH The posterior pituitary produces two peptide hormones that differ by only two AAs: oxytocin and anti-diuretic hormone (ADH). Both oxytocin and ADH are nonapeptides with a disulfide bridge. [11]  These nonapeptides are packaged through a process involving carrier proteins called neurophysins. [12]  

Insulin  is a 51 amino acid peptide hormone that consists of two disulfide-linked peptide chains. [12]  IGF-1 (insulin-like-growth-factor- 1) family are also peptide hormones but have three disulfide bonds. [12]  Insulin's role in the body is multifaceted to control metabolic homeostasis, including glucose uptake from the blood and storage of glucose as glycogen in the liver. 

Glucagon is created when proglucagon is cleaved by prohormone convertase 2, to form a fully processed bioactive peptide. [13]  It is released by pancreatic alpha cells in response to hypoglycemia or even during a homeostatic increase in concentrations of amino acids. [13]  Glucagon's effects to promote homeostatic equilibrium throughout the body, work through mechanisms that balance energy expenditure and glucose metabolism. The study of this peptide hormone and its mechanisms provides a basis of understanding of therapeutics for diabetes management and other conditions. [13]  

Secretin is another example of a peptide hormone, with an N-terminal and C-terminal end, composed of a 27 chain amino acid sequence. [14]  This peptide originates from the SCT gene, and first becomes a prohormone known as prosecretin. Once activated by exposure to gastric acid, it is cleaved into the active peptide form and released by S cells in the mucosa of the duodenum. [14]  It functions to stimulate the pancreas and bile ducts to release bicarbonate, which acts to neutralize potentially harmful gastric acids entering into the stomach. [15]

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide, which is most commonly localized to C and Aδ sensory fibers but affects both the central and peripheral nervous systems and metabolism through a multitude of receptor types. [16]  New research has demonstrated that intraperitoneal treatment with CGRP can have an energy stimulating effect and even promote an increased appetite. [17]  Current research has also linked the activity CGRP in the cerebrovascular system to a possible etiology of migraine attacks. [18]  CGRP is mainly found in the enteric nervous system but has been postulated to play a potential role in cranial nociception and cerebral vasodilation, leading to severe migraine headaches. [19]

Natriuretic Peptides are small peptide hormones secreted by cardiac myocytes in response to tension or wall stress. [20]  This peptide system, including atrial natriuretic peptides (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are all secreted by the cardiac atrium as protective mechanisms to prevent adverse cardiovascular/renal conditions including anti-proliferative, anti-remodeling, vasodilative, and modulation of the renin-angiotensin-aldosterone system. [20]  The peptide, ANP, is secreted in the atrium of cardiac tissue and is known to be 28 amino acids in length linked by disulfide bonds. [20]  BNP, on the other hand, shares 17 common amino acids with ANP but is a 32 amino acid peptide, while CNP is a total of 22 amino acids in length. [20]  Isolation and understanding of these peptide hormones have provided a better understanding of physiologic blood pressure control and an opportunity for natriuretic peptides for therapeutic purposes. [21]

  • Pathophysiology

Pathophysiological processes related to peptides are very broad due to the ubiquitous nature of peptides in the body. This section will describe how peptides are involved in the pathophysiology of various metabolic processes. 

Peptide-Receptor Complex and Signaling Cascade

Biologically active peptides are produced from genes that target specific proteins or protein-coupled receptors, such as G-protein-coupled-receptors (GPCRs). [22]  The combination of this peptide-receptor complex can then switch on or off a series of cascading reactions through a multitude of mechanisms. These downstream reactions that are activated may include other G-proteins, tyrosine kinases, and a series of transcription events and thus control all cellular processing and functioning. [22]  

In some cases, when a peptide binding to a receptor causing a pathologic "on" state, unregulated transcription and proliferation may ensue, leading to an oncologic state. These cellular processes may be left unchecked and result in tumor growth. The design of synthetic peptides, created to act as endogenous peptides do and bind to a target receptor, can identify the location of tumor growth for identification and even for therapeutic purposes. 


Peptides play a large endogenous role in humans and other species as a first-line barrier to fight infection. One of the components of the body's innate immune system includes the production of antimicrobial peptides (AMPs) in the epithelium. [23]  In addition to the epithelium, AMPs are also produced by neutrophils, mast cells, and even adipocytes  [24] . These AMPs can be post-translationally modified to fight a wide range of different infections, and with their cationic and interact with the negatively charged bacterial surface. A very important subset of AMPs is called defensins and cathelicidins. [24]  

Dermcidin is a known gene that encodes antimicrobial resistance peptides in the sweat glands that can survive at a high salt concentration and over a wide range of pH values. [25]  It is known that some bacteria can even produce their AMPs and develop resistance mechanisms to endogenous AMPs so that they can proteolytically cleave the peptides and survive. [24]

  • Clinical Significance

As previously mentioned, peptides play an essential role in many physiological processes present throughout the body. The clinical significance peptides will be summarized below including some dermatologic disease states as well as therapeutic uses of peptides as imaging probes related to oncology for imaging and tumor targeting. Note that the information provided is concise and is not intended to represent all physiological processes that involve peptides.

Wound repair

Endogenous peptides also play a role in wound healing, and induction of mesenchymal cells to differentiate and promote bacteriolysis within the wound and facilitate healing. Antimicrobial peptides from within wound fluid induced by known as syndecan, a cell surface heparan sulfate proteoglycan. [26]  Syndecan functions to activate heparin-binding growth factors and tissue matrix substances to facilitate wound repair in damaged tissues. [26]

Chronic Inflammatory Skin Conditions

As mentioned previously, healthy skin can secrete AMPs to defend against surface attack, especially by gram-positive and gram-negative bacteria, viruses, and fungi. [27]  It is shown that peptides play a role have a chronically disrupted epithelial microbiome which predisposes the tissue to pathogenic infection and persistence of inflammatory skin conditions. [28]  In the inflamed skin of atopic dermatitis patients compared to the inflamed skin of normal subjects, there is suppression for anti-microbial action due to the decreased expression of normal epidermal AMPs such as LL-37, β-defensin-2, and β-defensin-3. [28]  

Where atopic dermatitis patients have suppression of AMPs leading to a further inflammatory, infectious state, patients with rosacea overexpress an anti-microbial peptide known as cathelicidin anti-microbial peptide (CAMP). [27]  The metabolites and products of this peptide, CAMP, are what result in the inflammatory state of the epidermis. Knowing the pathway that stimulates CAMP expression in epidermal tissues to elevate anti-microbial peptide generation in an otherwise suppressed state such as atopic dermatitis, may provide a unique and novel therapeutic approach to improve the inflammatory state of patients with this condition. [27]  

Molecular Imaging and Tumor Targeting  

The mechanism of endogenous peptide and specific receptor binding is principally the design for peptides acting as imaging probes and receptor-binding peptides for overexpressed receptors such as in cancer proliferation. [29]  These probes may be strategically designed in vitro to mimic endogenous peptides that ultimately act as biomarkers and allow for the detection of a tumor. The implications of this advanced technology apply to the specific identification of tumor growth and even therapeutic purposes. With advancing sciences and molecular peptide chemistry and a better understanding of more effective targeting, these synthetic peptides have the potential to target multiple disease states with high specificity in imaging modalities such as PET/SPECT, optical imaging, and MRI. [29]  

As biochemical sciences and therapeutic design continue to progress, peptide synthesis and design are heavily studied with implications for oncologic therapy as the pharmaceutical industry continues to shift more toward biologicals for new drug candidates. [4]

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Disclosure: Jessica Forbes declares no relevant financial relationships with ineligible companies.

Disclosure: Karthik Krishnamurthy declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

  • Cite this Page Forbes J, Krishnamurthy K. Biochemistry, Peptide. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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  • Introduction to amino acids

Peptide bond formation

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Video transcript

Peptide Synthesis

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Peptide Synthesis

What is Peptide Synthesis?

Characterized by the formation of a peptide bond between two amino acids, peptide synthesis is, essentially, the production of peptides. Though peptide synthesis was somewhat hampered by relatively inefficient production practices at its inception, advancements in chemistry and technology have led to vastly improved synthesis methods. With the strong growth of the field of peptide science, it is clear that synthetic peptides will continue to play vital roles in areas of scientific and medical progress in the modern age.

Steps of Peptide Synthesis

How Peptides are Synthesized?

Peptides are synthesized by linking two amino acids together. This is most often accomplished by attaching the C-terminus, or carboxyl group, of one amino acid to the N-terminus, or amino group, of another. Unlike protein biosynthesis, which involves N-terminus to C-terminus linkage, peptide synthesis occurs in this C-to-N fashion.

Peptide Synthesizer

While there are twenty amino acids that occur commonly in the natural world (such as arginine, lysine, and glutamine), many other amino acids have also been synthesized. This allows for abundant possibilities in the creation of new peptides. However, amino acids have numerous reactive groups that can negatively interact during the synthesis process, leading to unwanted truncating or branching of the peptide chain or causing suboptimal purity or yield. As a result, peptide synthesis is a complex process that must be expertly carried out.

In order to ensure the desired outcome from the synthesis process and avoid extraneous, unwelcome reactions, certain amino acid reactive groups must be deactivated, or protected, from reacting. Thus, scientists have engineered special chemical groups designed to do just that. Called “protecting groups,” they can be separated into three categories:

N-terminal protecting groups – These groups protect the N-termini of amino acids. Referred to as temporary protecting groups, they are removed relatively easily to facilitate the formation of peptide bonds. Tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) are two frequently used N-terminal protecting groups.

C-terminal protecting groups – These groups protect the C-terminus of amino acids. The use of C-terminal protecting groups is warranted in liquid-phase peptide synthesis but not solid-phase peptide synthesis.

Side chain protecting groups – As amino acid side chains are quite conducive to reactivity during peptide synthesis, various unique side chain protecting groups are needed to protect against unwanted reactions. Able to remain intact during the many cycles of chemical treatment during synthesis, side chain protecting groups are known as permanent protecting groups. They are only removed with strong acids after the conclusion of peptide synthesis.

Peptide Synthesis Processes

The original approach to peptide synthesis was through a process known as solution phase synthesis (SPS). While SPS does have some merit today, notably in large-scale peptide production, it has largely been supplanted by solid-phase peptide synthesis, or SPPS. This is because SPPS offers several advantages, including high yield, purity, and speed of production.

SPPS involves five steps performed in a cyclical manner:

1. Attaching an amino acid to the polymer 2. Protection (to prevent unwanted reactions) 3. Coupling 4. Deprotection (to allow the attached acid to react to the next amino acid to be added on) 5. Polymer removal (resulting in a free peptide)

Additionally, SPPS synthesis can be further enhanced by the use of microwave-assisted SPPS. This is particularly useful when synthesizing long peptide sequences, as yield and speed can both be improved. However, microwave-assisted SPPS can be more expensive than traditional SPPS.

While peptide synthesis processes like SPPS offer excellent purity and yield standards, impurities and imperfections can still occur along the way. This likelihood increases with the length of the peptide sequence, as more steps are needed to complete synthesis. Therefore, certain purification techniques are utilized in order to ensure optimal quality. Among these are reverse-phase chromatography (RPC) and high-performance liquid chromatography (HPLC). Capitalizing on peptides’ physiochemical properties, these purification methods are able to separate impurities from the desired peptide. RPC is the most widely used peptide purification method today.

The Value of Synthetic Peptides

Peptides have proven to be critical elements of biomedical research, and peptide synthesis continues to fuel scientific progress worldwide. The therapeutic potential of peptides has drawn the attention of various pharmaceutical companies, and several drugs made from peptides have received FDA approval and reached the market. The efficacy, specificity, and low toxicity of peptides assures us that peptides will continue to be pursued and developed for pharmaceutical and diagnostic purposes and will remain a growing area of biochemical research.

Peptide Information

Written by Peptide Information


  1. Peptides Synthesis

    peptide synthesis

  2. Synthesis of Peptides

    peptide synthesis

  3. Peptide Synthesis

    peptide synthesis

  4. Long-peptide-synthesis-by-ligation

    peptide synthesis

  5. Synthesis procedure for peptide conjugates. (A) N-terminal peptide

    peptide synthesis

  6. solid phase peptide synthesis

    peptide synthesis


  1. merrifield peptide synthesis

  2. chemical synthesis of dipeptide and tripeptides


  4. Peptide Synthesis

  5. M Sc-Organic Biomolecules Amino acids -class-9-solid phase Peptide synthesis Q&A Dr. Hareesh Kumar P



  1. Introduction: Peptide Chemistry

    Methods combining the unmatched flexibility of chemical solid-phase peptide synthesis (SPPS) with the cost effectiveness of recombinant engineering can overcome this hurdle and provide on-demand access to custom synthetic proteins.

  2. Biochemistry, Peptide

    Peptide synthesis depends on three main reactions: 1. an amino acid goes through a deprotection step, a preparatory reaction that adds the next amino acid to the chain, and lastly, a coupling reaction that forms the final peptide with functionality. [1] . In the second step, the amino acid becomes activated with several reagents.

  3. Peptide bond formation (video)

    Peptide bond formation. Google Classroom. About. Transcript. How amino acids form peptide bonds (peptide linkages) through a condensation reaction (dehydration synthesis). Questions. Tips & Thanks. Want to join the conversation? Sort by: Top Voted. Gio. 8 years ago.

  4. Application of Peptides: An overview

    The routine synthesis of large polypeptides or small proteins of 30-100 amino acids has enhanced peptide applications. Synthetized Bioactive Peptides. Synthetic peptides and proteins also have their place in the market for which they have yielded billions of USDs.

  5. Peptide Synthesis

    Peptides are synthesized by linking two amino acids together. This is most often accomplished by attaching the C-terminus, or carboxyl group, of one amino acid to the N-terminus, or amino group, of another. Unlike protein biosynthesis, which involves N-terminus to C-terminus linkage, peptide synthesis occurs in this C-to-N fashion.