The pursuit of more effective, selective, and safer therapies is driving innovation in biopharmaceutical research, and unnatural amino acids (UAAs) have emerged as powerful tools in this endeavor. By expanding the chemical space beyond the 20 canonical amino acids, UAAs offer unprecedented opportunities to manipulate molecular properties and design next-generation therapeutics and diagnostic reagents.   

What are Unnatural Amino Acids?

Unnatural amino acids (UAAs) are non-proteinogenic amino acids that are not incorporated into proteins by the standard translation machinery of living cells. They can either be found in nature or synthesized in the laboratory, and they greatly expand the chemical space beyond the 20 canonical amino acids.   

What Unnatural Amino Acids are Available?

The versatility of UAAs lies in the ability to design and synthesize them with a wide variety of side chains, each with unique chemical and physical characteristics.   

There are several categories of UAAs, including:

· Chemically modified natural amino acids: This involves modifying the side chains of the 20 naturally occurring amino acids to introduce new properties.   

· Amino acids with novel side chains: This strategy focuses on designing and synthesizing amino acids with entirely new side chains, often incorporating functionalities not found in nature.   

· β-amino acids: Amino acids where the amino group is attached to the β-carbon instead of the α-carbon (e.g., β-alanine, used to increase peptide stability).   

· D-amino acids: These are mirror images of the natural L-amino acids.   

This structural diversity enables the introduction of specific reactivities, spectroscopic probes, or structural constraints into peptides and proteins. The distinct chemical structures of UAAs, engineered to possess a wide array of unique side chains, are key to their compelling properties, expanding beyond those of their natural counterparts.   

These can include:

· Bioorthogonal functionalities: Chemical groups that react selectively with each other under physiological conditions without interfering with native biological processes. This allows for precise labeling and conjugation of proteins within complex biological systems.   

· Spectroscopic probes: Fluorescent, phosphorescent, or other light-absorbing or emitting groups that enable the tracking and visualization of proteins in vitro and in vivo.   

· Post-translational modification mimics: Introducing amino acids that mimic phosphorylation, glycosylation, or other modifications can help study their effects or create more stable therapeutic proteins.   

· Novel steric and electronic properties: UAAs can be designed to fine-tune protein folding, stability, and interactions with target molecules, leading to enhanced lead optimization in drug development.   

The Applications of UAAs in Biopharmaceuticals

The impact of UAAs is already being felt across several key areas of biopharmaceuticals, which we will delve into in more detail in the following parts of this series:

· Targeted Drug Development: UAAs are enabling the creation of next-generation peptide-drug conjugates (PDCs) and other protein therapeutics with improved targeting specificity and reduced off-target toxicity. The ability to precisely control the site and stoichiometry of drug conjugation is revolutionizing how we approach cancer and other diseases.   

· Advanced Vaccine Development: UAAs are being employed to design more stable and immunogenic antigens, potentially leading to more effective vaccines against a range of infectious diseases. Strategies include enhancing antigen presentation and even creating self-adjuvanting vaccine candidates.   

· Cutting-Edge Diagnostic Reagents: UAAs are facilitating the development of highly sensitive and specific biosensors and imaging agents for early disease detection and monitoring. Their unique chemical handles allow for the attachment of diverse reporter molecules, enabling unprecedented insights into biological processes.   

The Future of UAAs

The field of unnatural amino acids is dynamic, with ongoing research focused on expanding their chemical diversity and overcoming synthetic challenges. Novel synthesis techniques such as Ni/Ag electrocatalytic cross-coupling are being developed to produce UAAs more efficiently. The integration of artificial intelligence and machine learning algorithms holds the potential to predict peptide-protein interactions and optimize peptide sequences containing UAAs for desired properties. The continued advancement of UAA technology holds immense promise for creating highly specific and effective therapies that address a wide range of medical challenges.   

Look out for part 2 of our UAA series "Beyond the 20” where we discuss the engineering potential for UAAs in targeted drug development.

If you would like to learn more about resources for advancing your pharmaceutical or diagnostic project, Biosynth have a wealth of expertise in designing and optimizing peptide design with the knowledge to help you choose the best UAA candidates for your work. Visit our site to find out more.