Amino Acids for Pharmaceutical Industry

Amino acids play a vital role in the pharmaceutical industry, especially in drug development, production and treatment. As a basic component of proteins and enzymes, amino acids not only play a central role in the structure and function of drugs but are also widely used in biopharmaceuticals, vaccine development and antibody-drug conjugate (ADC) design. In the pharmaceutical industry, amino acids are used not only for the synthesis of therapeutic proteins and vaccines, but also as excipients, stabilizers and components of drug delivery systems. In addition, the development of unnatural amino acids provides greater flexibility for drug design, especially in improving drug stability, solubility and targeting. Therefore, the research and application of amino acids are of great significance for improving the efficacy and safety of drugs and play a key role in promoting the development of new drugs and innovative treatment regimens.

What is an Amino Acid?

An amino acid is an organic compound that combines an amino and carboxyl group, and it is the fundamental unit of proteins. These amino acids adhere together through peptide bonds to create peptide chains, which fold up into functional proteins that carry out all kinds of biological tasks. Amino acids, which also participate in protein synthesis, are signalling molecules, cofactors of enzymes, neurotransmitters, and many other functions in the body, including metabolism, immunity, regulation, and more. Along with their physiological role in the body, amino acids have major roles in the pharmaceutical industry. These amino acid derivatives, for example, are used as drug carriers, synthetic peptide precursors, and in the synthesis of antibiotics and antivirals. Furthermore, amino acids and derivatives are widely used in the formulation of drugs for metabolic diseases, cancers and other ailments, particularly the research and development of peptide drugs and antibody therapeutics, in which amino acids are involved.

Fig. 1. Amino acid structure.

Structure of Amino Acid

Amino acids also have a universal structure that mostly consists of an amino group (-NH₂) and a carboxyl group (-COOH). The amino group (-NH₂) is a base and will bind to acidic elements; the carboxyl group is acidic. They bind together in a peptide bond, the building block of protein production. Each amino acid has a side chain (R group) that has different chemical properties depending on the type of amino acid and determines how the amino acid looks and how it folds and functions in proteins. Non-polar amino acids like alanine and phenylalanine, for instance, have side chains that don’t react in any meaningful way with water molecules, whereas polar amino acids like aspartic acid and glutamic acid have side chains that react with water. Aside from these simpler forms, amino acids generally come in L- and D-isoforms, with the L-form being the most common form in living organisms and the D-form confined to bacteria and some microbes. When it comes to proteins, L-amino acids take the lead role, helping to form peptide chains, which in turn influences the way the protein functions and shapes.

Benefits of Amino Acids

• Protein Synthesis: Amino acids compose proteins, they’re produced by tying different amino acids together in the form of peptides. This order and mixture of amino acids are what define protein structure and function. Proteins are not just building blocks of cells, they also catalyse reactions, immune systems and hormone control.
• Metabolic Regulation: Amino acids are signaling molecules and regulators of metabolism in the body. Some amino acids, for instance, contribute to growth hormone production, or to the production of insulin, which is what regulates blood sugar levels.
• Neural Function: Amino acids are also crucial in neurotransmission. For example, glutamate, an excitatory neurotransmitter, is involved in nerve signal transmission, while gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter.
• Antioxidant Effects: Some amino acids are antioxidants. For example, cysteine helps to make glutathione, which is involved in the antioxidant response.
• Energy Supply: During periods of hunger or extreme conditions, amino acids can be broken down into glucose or fatty acids to provide energy for the body.

What are Amino Acids Made of?

The manufacturing of amino acids began in 1820 with the hydrolysis of proteins, followed by the chemical synthesis of amino acids in 1850. In 1957, Japan successfully produced glutamic acid using fermentation, which also promoted the development of the global amino acid industry. Currently, there are two main types of production methods for amino acids: synthetic methods and hydrolysis methods. Synthetic methods can be further divided into biosynthesis (also known as biological fermentation) and chemical synthesis.

• Amino Acid Hydrolysis

The extraction of amino acids from protein hydrolysis products is mainly applicable to large-scale industrial production of specific amino acids, such as L-cysteine, L-leucine, and L-tyrosine. This method takes advantage of differences in the physical and chemical properties of amino acids (such as chemical affinity and pH) to separate and purify them. For example, L-cysteine can be extracted from keratin in animal feathers, hair, manes, and hooves using activated carbon and concentrated hydrochloric acid. The main advantage of this method is that it utilizes industrial by-products or waste, but the use of highly concentrated acids and bases may reduce amino acid yields.

• Amino Acid Synthesis

Historically, chemical synthesis has been the classic method for producing non-chiral amino acids, such as glycine or the racemic mixtures of D,L-methionine or D,L-alanine. The first amino acid synthesis, the Strecker synthesis reaction, was reported in 1850. Through this reaction, aldehydes, ketones, amines, and other compounds are converted into α-amino acids using acid catalysts, metal cyanides, and water. Another example includes the reaction of aldehydes with hydrogen cyanide and D-α-methylbenzylamine in methanol, followed by hydrolysis to produce amino nitriles that are converted into N-α-methylbenzyl amino acids. The reaction can then undergo catalytic hydrogenolysis to remove the methylbenzyl group from the amino acid molecules. This pathway is clear, efficient, and favorable for purification. Another example of chemical synthesis is the ammonia hydrolysis of trichloroethylene to produce glycine, or the ammonia hydrolysis of (±)-2-chloropropionic acid to yield D,L-alanine. However, chemical synthesis is not without drawbacks, such as the high cost of catalysts used and the danger of cyanide in the reactions. Additionally, the Strecker synthesis is not enantioselective, producing only racemic mixtures of D and L forms of amino acids. Nevertheless, advances in science have led to the gradual use of safer catalysts.

• Amino Acid Fermentation

Enzyme-catalyzed processes are based on enzymes or their combinations to catalyze the production of the desired amino acids. For example, L-aspartic acid can be obtained from fumaric acid through the action of L-aspartate ammonia-lyase. Commonly used enzymes include hydrolases, ammonia-lyases, and NAD+-dependent L-amino acid dehydrogenases. Most of these enzymes are derived from microorganisms such as Escherichia coli, Saccharomyces cerevisiae, Pseudomonas putida, and Cryptococcus neoformans. It is estimated that strains of E. coli and Corynebacterium glutamicum contribute approximately 6 million tons of L-glutamic acid and L-lysine annually. The main advantage of enzyme-catalyzed pathways is that they can produce higher concentrations of D- and L-amino acids with fewer by-products. However, the high demand for enzymes and substrates in large-scale production, along with the high cost of enzymes and their limited stability, are significant drawbacks. To improve the performance of these processes, various technologies based on immobilized biocatalysts have been developed for the production of products such as L-aspartic acid and L-alanine.

Natural Amino Acids

Natural amino acids refer to those that are widely found in nature and synthesized within organisms through the protein synthesis pathways. They are the fundamental building blocks of proteins, and organisms arrange these amino acids in specific sequences through transcription and translation processes to form proteins with biological functions. Common natural amino acids include alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), and phenylalanine (Phe), all of which play important roles not only in protein construction but also in metabolism, signaling, immune responses, and other processes. The production of natural amino acids typically relies on gene-encoded metabolic pathways, achieved through biosynthesis or microbial fermentation.

Unnatural Amino Acids

Non-natural amino acids are amino acid derivatives produced through synthetic or genetic engineering techniques, and are typically not directly found in nature. These amino acids have the characteristic of being able to replace natural amino acids under specific conditions or to confer specific functions by modifying their chemical structure. For example, D-amino acids are widely used in drug design and protein engineering because they are relatively rare in natural amino acids and possess better stability and resistance to degradation. Additionally, amino acid derivatives such as thioamino acids and aromatic amino acids are also applied in industrial and pharmaceutical fields, particularly in the design of proteins with specific functions, targeted drug development, and the manufacturing of novel materials. Non-natural amino acids offer extensive possibilities for diversifying protein functions, innovating targeted therapies, and other applications.

What Do Amino Acids Do?

Amino acids of nature and synthetic origin are widely used in medicine. Natural amino acids are used in drug design and protein engineering to produce peptide drugs, antibodies, and biologics. For instance, they are produced as antimicrobial peptides, immunosuppressants, and anticancer drugs. It also uses derivatives of natural amino acids like glutamic acid and lysine as drug carriers. Non-natural amino acids hold more functional opportunities for drugs still. Unnatural amino acids obtained from genetic engineering or chemical synthesis could then be engineered to build molecules of drugs that were more stable, specific and resistant to degradation. Not only that, non-natural amino acids are commonly used in designing and functionalising small molecules for better pharmacokinetics.

• Amino Acids for Disease Treatment

Amino acids and their derivatives can help treat various diseases through direct or indirect biological actions. Certain amino acids, such as glutamate and tryptophan, are involved in neurotransmission and can be used in the treatment of neurodegenerative diseases and depression. Additionally, amino acids play a role in the metabolism of tumor cells, regulating cell proliferation, and have become an important area of research in cancer therapy. Amino acids are also widely used in immune modulation, metabolic disorders, and as adjunctive treatments for other diseases.

• Amino Acids for Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) have emerged as promising biopharmaceuticals for cancer treatment. Amino acids play an essential role in ADC design, as they are used in antibody conjugation modifications and in linking antibodies to cytotoxic drugs. By selectively targeting drug molecules to cancer cells, ADCs can improve therapeutic precision and reduce toxicity to normal cells. Amino acids or their derivatives serve as linkers, typically covalently bonded to both the antibody and the drug, aiding in targeted drug release. The chemical properties of amino acids enable these conjugates to have better stability and controllable drug release characteristics in the body.

• Amino Acids for Chiral Drugs

Chiral drugs are crucial in drug design because their different isomers may have varying biological activities and side effects. Amino acids themselves are natural chiral molecules and are widely used in the synthesis of chiral drugs. For example, drugs synthesized based on amino acids may have higher selectivity and biological activity, while optimizing their chiral structure can significantly reduce side effects. In the development of chiral drugs, amino acids help prepare more effective drug molecules due to their unique stereochemical properties.

• Amino Acids for Inhibitors

Amino acids and their derivatives are often essential components of inhibitors, particularly in the synthesis of enzyme inhibitors, receptor antagonists, and other drugs. For instance, in cancer and antiviral treatments, modulating the structure of amino acids helps design highly specific inhibitors that selectively block pathological processes and suppress adverse physiological reactions. Modifications like acylation or methylation of amino acids can enhance their binding affinity to targets, thereby improving drug efficacy.

• Amino Acids for Pharmaceutical Intermediates

Amino acids serve as important intermediates in drug synthesis, playing a crucial bridging role in many drug production processes. Through derivatization reactions of amino acids, many active drug molecules or their precursors can be synthesized. For example, amino acid derivatives are key intermediates in the synthesis of antibiotics, antiviral drugs, and anticancer drugs, providing the necessary structural foundation for the drugs’ final biological activity.

• Amino Acids for Drug Delivery

The excellent biocompatibility of amino acids makes them ideal components in drug delivery systems. In targeted drug delivery systems, amino acids or their derivatives can enhance drug bioavailability and improve distribution within the body, thereby increasing therapeutic efficacy. Amino acids’ carrier function helps drugs cross biological membranes, especially when delivering large-molecule drugs (such as protein drugs and nucleic acid drugs), and their chemical properties can further control the drug release rate and targeting.

• Amino Acids for Sustained-Release Injectables

Extended-release injectables can achieve long-term treatment by gradually releasing the drug. Amino acids and their derivatives play a significant role in extended-release injectables due to their adjustable solubility, stability, and biocompatibility. By modulating the molecular structure of amino acids, the drug release rate within the body can be controlled, reducing injection frequency and improving therapeutic outcomes. This slow-release effect is particularly promising for chronic diseases and long-term treatments.

• Amino Acids for Prodrug Development

A prodrug is a compound that is inactive but can be metabolized into an active drug in the body via enzymatic or other biological reactions. Amino acids play a crucial role in prodrug development. By linking active drug molecules with amino acids, the stability and bioavailability of drugs can be improved, and their duration of action in the body can be extended. Common applications include amino acid-based prodrugs for treating diseases such as diabetes and cancer, where specific enzymes or reactions convert them into active ingredients.

• Amino Acids for Peptide Drugs

Amino acids are the building blocks of peptide drugs. Peptide drugs, due to their high selectivity and low toxicity, have significant potential in treating a variety of diseases. Amino acids serve as fundamental structural units in peptide drugs, and by arranging peptide chains in different combinations, therapeutic peptides targeting specific pathways can be designed. These peptide drugs are widely applied in cancer, infection, and immune regulation, with the type and sequence of amino acids directly influencing the specificity and efficacy of the peptide drugs.

• Amino Acids for Antimicrobial Agents

Antimicrobial drugs play an important role in modern medicine. Amino acids and their derivatives are often used as the primary active ingredients or excipients in the development of antimicrobial agents. Certain amino acids possess natural antibacterial and antiviral properties, helping to address the threat of drug-resistant microorganisms. By modifying the structure of amino acids, their antimicrobial activity can be enhanced, leading to the development of broad-spectrum antimicrobial drugs.

• Amino Acids for Amino Acid Injections

Amino acid injectables are clinically used to treat malnutrition, liver and kidney dysfunction, and other diseases. These injectables provide essential amino acids to support normal physiological functions. In such injectables, amino acids not only supplement the diet but also enhance metabolic reactions, promoting the repair and recovery of tissues in the body.

• Amino Acids for Cocrystal Development

Pharmaceutical co-crystals are a strategy to improve the solubility, stability, and bioavailability of drugs by forming co-crystals with drug molecules. Due to their good solubility and crystallization properties, amino acids are widely used in co-crystal drug development. By forming co-crystals with other drug components, amino acids can enhance the physicochemical properties of drugs, improving their clinical effectiveness.

• Amino Acids for Pharmaceutical Excipients

Amino acids play an important role as excipients in drug formulations. They not only improve drug solubility and stability but also enhance drug absorption and metabolism. In many oral drugs, injectables, and extended-release formulations, the use of amino acids as excipients helps improve the manufacturing process and clinical outcomes.

• Amino Acids for Active Pharmaceutical Ingredients

Amino acids serve as active pharmaceutical ingredients (APIs) or their precursors in the synthesis of many drugs. In the production of antitumor, antiviral, and antimicrobial drugs, amino acids are indispensable raw materials. Through chemical modification, amino acids can be converted into drugs with specific biological activities, widely used in the treatment of various diseases.

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