Amino Acids for Peptide Drugs

Amino acids are the fundamental building blocks of peptide drugs, and in recent years, they have become a focal point in drug development due to their potential in treating various diseases. Peptide drugs are composed of short chains of amino acids, which exhibit high specificity and low toxicity, providing more precise treatment options compared to traditional small molecule drugs. The selection of amino acids and sequence modifications have a significant impact on the pharmacokinetics, stability, and efficacy of peptide drugs. A deep understanding of the unique properties of amino acids, such as their ability to form specific secondary structures and interact with biological targets, is essential for designing effective peptide drugs. Moreover, advancements in synthetic biology and peptide chemistry have made the use of non-natural amino acids possible, further enhancing the stability, solubility, and resistance to enzymatic degradation of drugs.

What are Peptide Drugs?

Peptide drugs are active molecules based on many amino acids bonded through peptide bonds. Generally, they're 10 to 100 amino acids, with a molecular mass of less than 10,000. Most peptide drugs are derived from natural or endogenous peptides and so they have few or no negative effects in the body. Peptide drugs are more stable, more pure, cheaper to produce, and less immunogenic than proteins. This accelerated and matured technology of peptide synthesis has rendered peptide drugs the focus of biopharmaceutical research in recent years. Today, there are peptide drugs that are applied to cancer, autoimmune conditions, heart diseases, diabetes and more, with a multitude of uses.

Fig. 1. Peptide drugs.

Advantages of Peptide Drugs

Comparable to chemical drugs and proteins, peptide drugs have a molecular weight somewhere in the middle between, so they are both. They have the stability, purity and stability-controlled characteristics of small molecule drugs but with the high specificity and biological activity of protein drugs. But because they are complex to make, peptide drugs can be pricey. These are the main strengths of peptide drugs, being selective and specific, and being very effective at extremely low concentrations. Activated ligands in normal physiological regulation (eg, hormones or neurotransmitters) perform physiological regulation by binding to receptors in a specific way. Peptide drugs, in use in medicine, mimic these physiological activities by interacting with receptors at the cell membrane's surface to induce their therapeutic effects. Their structure is almost identical to physiological active molecules that exist naturally, and they are very specific and selective. Peptide drugs are better efficacious than small molecules, and most average doses are from micrograms to milligrams, effective even at low concentrations. They are also easily metabolised, so they don't leave an accumulation of toxicity or unintended side effects. Peptide drugs are immunogenically less virulent, more storage friendly, cheaper to produce, and easier to patent compared with recombinant proteins and monoclonal antibodies.

Peptide Based Drug Design

Peptide drugs offer greater efficiency, safety, and tolerability compared to chemical drugs, along with higher selectivity and lower risk of accumulation in the body. However, peptide drugs also have clear drawbacks. Compared to chemical drugs, peptide drugs have unstable physicochemical properties, are prone to oxidation and hydrolysis, tend to aggregate, have a short half-life, are cleared quickly, and have difficulty crossing cell membranes. Additionally, most peptide drugs cannot be taken orally. Therefore, rational design is essential to overcome these limitations and optimize peptide drug performance.

• Enhancing Stability

The stability of peptide drugs is a key factor limiting their development. Researchers are working to optimize stability by modifying the peptide structure and introducing barriers. Approaches include cyclizing the peptides, modifying the amino acid backbone, incorporating non-natural amino acids, replacing certain amino acids, and coupling structures such as polyethylene glycol (PEG), lipids, and proteins to extend the half-life of the peptide and increase stability, reducing the frequency of injections.

• Oral Administration System

By combining peptide drugs with permeation enhancers, the permeability of the intestinal mucosa can be increased, allowing peptide drugs to quickly pass through the intestinal wall and be absorbed into the bloodstream for oral administration. However, the effectiveness of oral administration is generally lower than that of injection. In 2019, Novo Nordisk's oral semaglutide was approved, becoming the only oral GLP-1 drug and making an impact on the market. However, clinical data shows a bioavailability of only around 1%, with several limitations during administration. Despite these challenges, oral peptide drugs remain an important research direction as breakthroughs continue.

• Injectable Drug Delivery System

This approach involves encapsulating peptides in high-molecular substances to protect them from contact with proteases, thereby safeguarding the peptides. Current applications include injectable microspheres, and research is also exploring the embedding of peptides in liposomes for sustained release via intravenous injection.

• Peptide Conjugate Drug

Peptide-drug conjugates (PDCs) involve linking target-specific peptides with small molecule drugs to develop targeted therapies (primarily for cancer). In radiolabeled conjugates, peptides are linked to radioactive isotopes used to mark or kill tumors. In peptide-oligonucleotide conjugates, target-specific peptides are coupled with oligonucleotides to regulate gene expression, including antisense oligonucleotides and small interfering RNAs (siRNAs).

Peptide Drug Synthesis

The emergence of new chemical and biosynthetic processes has made large-scale production of peptides possible. Currently, over 100 peptide drugs have entered clinical trials, with a significant number in clinical development. Peptide-based discovery methods are becoming valuable tools for addressing several unresolved areas in disease treatment. Peptide biosynthesis involves various methods, and one of the main production strategies is through recombinant technology. Here are some key methods for peptide biosynthesis:

• Chemical Synthesis: Chemical synthesis is the preferred method for preparing short and medium-length peptides. This approach allows for the introduction of non-natural amino acids and other general synthetic building blocks, offering a convenient, efficient, and automatable process. Chemical synthesis can be used to produce peptides on a small scale, but it remains challenging for long peptides.
• Recombinant DNA Technology: Recombinant DNA technology enables the synthesis of peptides in expression systems such as E. coli, yeast, and mammalian cells. This method involves inserting the gene encoding the target peptide into an expression host, allowing it to produce and secrete the peptide. This technique is commonly used for producing medium-length peptides and large-scale manufacturing.
• Expanding the Genetic Code: Expanding the natural genetic code involves introducing novel non-canonical amino acids (ncAAs) during protein translation. This can be achieved using unique codons, orthogonal tRNAs, and orthogonal aminoacyl-tRNA synthetases. Expanding the genetic code provides a way to introduce amino acids with new chemical and physical properties, thereby increasing the diversity of peptides.
• Enzymatic Synthesis: Enzymatic synthesis utilizes enzymes to catalyze the formation of peptides within a biological system. This may include enzyme-catalyzed reactions on natural or synthetic precursor peptides, generating the target peptide through chemical methods.
• Fermentation: Fermentation in microorganisms or other biological systems can be used to produce peptides. This typically involves using suitable production strains, along with culture conditions and genetic engineering techniques to enhance peptide yield.

Amino Acids for Peptide Synthesis

BOC Sciences has strong capabilities in amino acid synthesis, particularly in providing custom synthesis services for non-natural amino acids. We utilize advanced synthetic technologies to supply high-quality natural and non-natural amino acids to support the development of peptide drugs. Through precise amino acid design and optimization, we can meet the diverse needs of drug development, ensuring the maximization of peptides' pharmacological properties, stability, and efficacy. Whether for conventional amino acids or functionalized, modified non-natural amino acids, BOC Sciences offers high-purity products that meet cGMP standards.

Peptide Drug Modification

The use of peptides is often hindered by poor permeability, low oral bioavailability, and low stability in the body. However, extensive research into peptide modifications has shown that these limitations can be overcome. Peptide modification is an important drug chemistry technique aimed at enhancing the biological activity, stability, and solubility of peptides, as well as achieving selectivity for peptide drugs. Here are some major strategies for peptide modifications:

• Backbone Modification: One of the goals of backbone modification is to enhance the proteolytic stability of peptides. This includes substituting L-amino acids with D-amino acids, inserting methylated amino acids, and introducing β-amino acids and pseudo-peptides. By incorporating these non-natural amino acids, particularly at proteolytic cleavage sites, the plasma half-life of peptide drugs can be effectively extended. For example, the selective vasopressin analog successfully extended its plasma half-life using this strategy.
• Side Chain Modification: Side chain modifications involve substituting natural amino acids with side chain analogs during peptide synthesis to improve binding affinity and target selectivity. Common side chain modifications include high-affinity arginines, phenylmethoxy tyrosines, and β-phenylalanines. GLP-1 analog drugs such as liraglutide and semaglutide have undergone side chain modifications.
• Simulating and Stabilizing Secondary Structures through Backbone and Side Chain Modifications: Due to weak interactions within peptides that are insufficient to form stable secondary structures, additional modifications to the backbone, N-terminus, C-terminus, or side chains are required. This can include mimicking the structure of natural products or protein-protein interaction hotspots to stabilize the secondary structure, ultimately generating promising peptide drug candidates.
• Peptide Cyclization: Cyclization is a common peptide modification technique that can be achieved through various strategies, such as head-to-tail, backbone-to-side chain, or side chain-to-side chain cyclization. Peptide cyclization helps increase proteolytic stability and cell permeability, while also allowing for the simulation and stabilization of secondary structures. Cyclization is also frequently used to stabilize other secondary structures, such as α-helices and β-sheets.

What is Peptide Drug Used For?

Peptides are compounds formed by linking multiple amino acids through peptide bonds via dehydration condensation. Peptides with fewer than 10 amino acids are called oligopeptides, those with 10 to 50 amino acids are referred to as polypeptides, and those with more than 50 amino acids are classified as proteins. Polypeptides play a crucial role in regulating various physiological functions in the human body, such as thyroid hormones, insulin, and growth factors, all of which are polypeptide substances. Peptide drugs have a molecular weight between that of biologics and chemical drugs. They primarily come from endogenous polypeptides or other natural polypeptides, and they exert effects on various circulatory systems to treat corresponding diseases. Based on their functions, peptide drugs can be categorized into peptide vaccines, antitumor peptides, antiviral peptides, peptide-targeted drugs, cytokine mimetic peptides, antimicrobial peptides, diagnostic peptides, and more. These drugs are mainly used for the treatment of diseases such as asthma, allergies, hepatitis, HIV/AIDS, tumors, and diabetes.

• Antimicrobial Peptides

The discovery and use of non-protein peptide antibiotics have made significant progress in combating bacterial infections. These peptide antibiotics include actinomycin, bacitracin, polymyxin A, polymyxin B, polymyxin B1, and polymyxin B2, which have shown efficacy against both Gram-negative and Gram-positive bacteria. The mechanism of action of antimicrobial peptides primarily involves disrupting the bacterial cell membrane, leading to cell death. While most peptide antibiotics are considered milestones in combating infections, they are not without limitations. Many exhibit cytotoxicity, which restricts their systemic use, leading to local application or repurposing for other treatments, such as cancer therapy (e.g., actinomycin). Currently, drugs like Vancomycin, Teicoplanin, Gramicidin D, Daptomycin, Oritavancin, Dalbavancin, and Telavancin have been successfully approved for human therapeutic use.

• Antiviral Drugs

Today, viral infections remain one of the leading causes of disease-related deaths. Antiviral drugs, along with vaccines, play a vital role in combating these diseases. Many peptides derived from natural sources, such as insect and reptile venom, can affect various stages of the viral lifecycle. Furthermore, short peptides derived from key viral proteins, when appropriately modified (e.g., through lipid insertion and cell-penetrating sequences), have led to the discovery of potent antiviral inhibitors. Naturally occurring antiviral peptide derivatives typically exhibit excellent resistance to degradation and stability under extreme temperature and pH conditions. Over the past 20 years, extensive research has developed antiviral therapies and prevention strategies for human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Some drugs developed for treating HIV infections have been shown to inhibit other viruses as well, and innovative methods used in antiretroviral therapy have been applied to the development of various treatment strategies.

• Antitumor Agents

Peptides have generated significant attention in oncology. They can serve as antitumor drugs, directly inducing cancer cell death, or be combined with chemotherapy drugs to selectively target tumor cells. Since the discovery of the first peptide with cytotoxic activity, many anticancer peptides (ACPs) have been isolated from living organisms or modified. Carfilzomib is a valuable success example — this second-generation proteasome inhibitor was FDA-approved in 2012 for the treatment of relapsed and/or refractory multiple myeloma. Carfilzomib is a tetrapeptide epoxyketone whose structure is derived from the modification of epoxomycin, a natural product isolated from actinobacteria with anti-inflammatory and proteasome inhibitory activities.

• Metabolic-Related Diseases

Obesity is a pathological condition characterized by the excessive accumulation of fat tissue, with severe health consequences. In recent years, Asokan's research team has demonstrated that a tetrapeptide (ValHisValVal) extracted from soybean protein can stimulate the lipolysis of skeletal muscle induced by a high-fat diet. Additionally, ValHisValVal peptide is responsible for regulating TNF-α levels, which are elevated in obese individuals. Furthermore, LeuProTyrProArg, a peptide derived from soybean glycine, exhibits appetite-modulating activity; it can lower serum triglycerides and cholesterol without affecting other body proteins.

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