Utilization of Unusual Nonproteinogenic Amino Acids: A New Paradigm for Natural Products Drug Discovery

Nonproteinogenic amino acids (NPAAs) have become essential in developing small molecules, peptides, and proteins as modern‐day chemistry and biology have progressed. The distribution, pharmacological functions, and metabolism of naturally occurring NPAAs are primarily unknown compared to the better‐studied proteinogenic amino acids; however, natural NPAAs vastly outnumber the well‐known 22 proteinogenic amino acids. The incorporation of NPAAs can significantly affect the stability, potency, and bioavailability of drugs or drugs‐like candidates. The primary goal of this review is to compile and summarize the current knowledge on naturally occurring NPAAs, with a particular focus on their sources, biological functions, and potential therapeutic applications. A secondary objective is to demonstrate how little we know about the nutritional benefits of NPAAs, as well as how documented toxicity could be used in therapeutic development.