Exploring Aspartate Transcarbamoylase: A Promising Broad-Spectrum Target for Drug Development

Pyrimidine nucleotides are essential for a wide variety of cellular processes and are synthesized either via a salvage pathway or through de novo biosynthesis. The latter is particularly important in proliferating cells, such as infectious diseases and cancer cells. Aspartate transcarbamoylase (ATCase) catalyzes the first committed and rate-limiting step in the de novo pyrimidine biosynthesis pathway, making it an attractive therapeutic target for various diseases. This review summarizes the development of a series of allosteric ATCase inhibitors, advancing them as potential candidates for malarial, tuberculosis and cancer therapies. Furthermore, it explores the potential for these compounds to be expanded into drugs targeting neglected tropical diseases, antimicrobial-resistant infections caused by the ESKAPE pathogens, and their possible application as herbicides. We identify the likely equivalent allosteric pocket in these systems and perform a structure and sequence-based analysis of the residues comprising it, providing a rationale for continued exploration of this compound series as both specific and broad-range inhibitors. The review concludes by emphasizing the importance of continued research into ATCase inhibitors, given their potential broad applicability in treating diverse diseases to enhance both human health and agricultural practices.