Natural products targeting the metabolism of amino acids: from discovery to synthetic development

Covering: up to 2025Amino acids constitute the essential components of biological systems. Over the recent years, there has been a growing interest in exploring amino acid metabolism as a source of novel druggable targets for intractable diseases such as cancer, metabolic disorders, and degenerative diseases. Culminating research has unveiled novel therapeutic targets associated with amino acid metabolism, including glutamine, cysteine, arginine, and tryptophan metabolism. The pursuit of therapeutic drug targets has resulted in the discovery of potential modulators showing promise for the development of new drug candidates. Many of these modulators have been derived from natural products, employing diverse methods such as traditional medical knowledge, high-throughput screening, and bioinformatics approaches. Based on these discoveries, a variety of synthetic analogues have been developed to improve pharmacological profiles, target selectivity, and drug-like properties. Structural optimization of natural product scaffolds, including derivatization, bioisostere incorporation, and prodrug strategies, has enabled the rational design of potent inhibitors targeting amino acid metabolism. These efforts have expanded the utility of naturally occurring inhibitors, offering enhanced efficacy and therapeutic potential. In this review, we systematically categorize natural products that target enzymes involved in amino acid metabolism, highlighting the recent advances in their development as medicinal agents. This work aims to provide a valuable resource for researchers by outlining the therapeutic potential of natural products and identifying opportunities for future investigation.