Antifungals targeted to protein modification: focus on protein N-myristoyltransferase

Abstract

Invasive fungal infections have increased dramatically in recent years to become important causes of morbidity and mortality in hospitalised patients. Currently available antifungal drugs for such infections essentially have three molecular targets: 14α demethylase (azoles), ergosterol (polyenes) and β-1,3-glucan synthase (echinocandins). The first is a fungistatic target vulnerable to resistance development; the second, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity; the third, a fungistatic (Aspergillus) or fungicidal (Candida) target, has limited activity spectrum (gaps: Cryptococcus, emerging fungi) and potential host toxicity that might preclude dose escalation. Drugs aimed at totally new targets are thus needed to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Protein N-myristoylation, the cotranslational transfer of the 14-carbon saturated fatty acid myristate from CoA to the amino-terminal glycine of several fungal proteins such as the ADP-ribosylation factor (ARF), presents such an attractive new target. The reaction, catalysed by myristoyl-CoA:protein N-myristoyltransferase (NMT), is essential for viability, is biochemically tractable and has proven potential for selectivity. In the past five years, a number of selective inhibitors of the fungal enzyme, some with potent, broad spectrum antifungal activity, have been reported: myristate analogues, myristoylpeptide derivatives, histidine analogues (peptidomimetics), aminobenzothiazoles, quinolines and benzofurans. A major development has been the publication of the crystal structure of Candida albicans and Saccharomyces cerevisiae NMTs, which has allowed virtual docking of inhibitors on the enzyme and refinement of structure–activity relationships of lead compounds.