Sterol biosynthesis inhibitors: Potential for transition state analogs and mechanism-based inactivators targeted at sterol methyltransferase

Sterol biosynthesis inhibitors (SBIs), discovered in the late 1960s and subsequently used commercially to treat ergosterol-dependent fungal diseases, represent a unique drug class targeted at an enzyme in a biosynthetic pathway. To date, few drugs have been commercialized as enzyme inhibitors; yet, prescription of SBIs has emerged as the gold standard for some cases of non-life-threatening antifungal chemotherapy and in crop protection. SBIs are not designed for their structural resemblance to the sterol molecule; they nonetheless can engender a curative effect by interfering with sterol production and homeostasis in the pathogenic organism. The increased use of SBIs in recent years, particularly the azole antifungals, has resulted in the development of resistance to those drugs, necessitating additional work to further our understanding of antifungal resistance and to explore opportunities to develop new enzyme inhibitors and uncover new enzyme targets that can regulate carbon flux in the post-lanosterol/cycloartenol pathway. This article reports general considerations for enzyme mechanism and active-site probes using inhibitors of the C-methylation reaction, including a potential new class of antifungal/antiparasitic agents of phytosterol synthesis tailored as mechanism-based inactivators. These steroid-based compounds prepared with different sterol side chain functionalities are designed to reversibly or irreversibly impair the sterol methyltransferase, an enzyme expressed in pathogenic microbes and plants but not in the human host. The salient aspects of these and related topics directed toward the enzyme recognition of sterol structure, and the inhibitory properties and catalytic competence of a series of specifically modified substrate analogs that affect sterol methyltransferase action are discussed.