Abstract

N-Glycosylation is a fundamental post-translational modification that regulates the folding, stability, and trafficking of many oncogenic receptor proteins. The extent and structural complexity of N-glycans on these receptors are closely associated with tumor growth, progression, and metastatic potential, making this pathway an attractive therapeutic target. Although numerous glycosyltransferases participate in N-glycan biosynthesis, the selective and therapeutically effective inhibition of specific enzymes within this pathway remains a significant challenge in medicinal chemistry. The natural product tunicamycin inhibits DPAGT1, the first enzyme committed in N-glycan biosynthesis, thereby disrupting glycoprotein maturation in malignant cells. However, its promiscuous cytotoxicity, lack of selectivity, and suboptimal drug-like physicochemical properties have limited its clinical translation. In contrast, muraymycin A1 has emerged as a non-cytotoxic nucleoside antibiotic with potent and more selective DPAGT1 inhibitory activity. Importantly, muraymycin A1 and its analogues demonstrate significant antiproliferative and antimetastatic effects in DPAGT1-dependent solid tumors while exhibiting minimal toxicity toward normal cells, suggesting a therapeutically exploitable window. This short review highlights recent advances in the structural, mechanistic, and pharmacological characterization of muraymycin-based inhibitors, with an emphasis on their selectivity, improved biological profiles, and emerging translational potential. Together, these developments support targeting early steps in N-glycan biosynthesis as a promising strategy for anticancer drug discovery and future clinical applications.

Keywords:N-Glycosylation; DPAGT1 inhibition; Glycoprotein biosynthesis; Glycosyl transferase targeting; Antiproliferative agents; Antimetastatic activity; Nucleoside antibiotics; Non-cytotoxic agents