Antifungals, squalene epoxidase

It is a synthetic allylamine derivative, which exerts its antifungal effect by inhibiting squalene epoxidase leading to deficiency of ergosterol and corresponding accumulation of squalene which causes fungal cell death. 

Naftifine hydrochloride and terbinafine (Lamisil) are allylamines that are highly active against dermatophytes but less active against yeasts. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48-1). 

G Petranyi, NS Ryder, A Stutz. Allylamine derivatives new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224 1239-1241,1984. 

Inhibitors of squalene epoxidase are used in antifungal drugs to treat athlete s foot, jock itch, ringworm, and nail infections. The drug Tinactin (tolnaf-tate) inhibits squalene epoxidase, which blocks the synthesis of the steroids the fungus needs to make its cell membrane. The defective cell membrane kills the fungus. 

Antifungal Fungal squalene epoxidase Terbinafine, naftifine... 

A schematic of fungal ergosterol biosynthesis starting from squalene is shown in Figure 40.1. The biosynthetic pathway has been simplified to emphasize steps important to the action of currently employed antifungal drugs. The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon squalene. Squalene is converted to squalene epoxide by the enzyme squalene epoxidase. Squalene epoxide is then cyclized to lanosterol, the first steroid in the biosynthetic pathway. The... 

Since ergosterol is used in the formation of the leishmanial cell membrane, inhibition of ergosterol biosynthesis has been considered as a useful target for chemotherapeutic attack. Allylamines (eg. terbinafine) and imidazole antifungals (eg. ketoconazole) have been found to interfere with different steps in the biosynthetic pathway of C28 sterols in leishmania and fungi. Allylamines inhibit the microsomal squalene 2,3-epoxidase and, therefore, inhibit the synthesis of squalene epoxide, the precursor of lanosterol. Imidazoles, on other hand, inhibit cytochrome P-450 dependent C-14 demethylation of lanosterol leading to decreased or no synthesis of ergosterol [30]. 

Naftifine, a broad-spectrum antifungal agent, is a synthetic allylamine derivative that interferes with sterol biosynthesis by inhibiting the enzyme squalene 2,3-epoxidase. This inhibition of enzyme activity results in decreased amounts of sterols, especially ergosterol, and a corresponding accumulation of squalene in the cells. 

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