Recent Advances in The Discovery of N‐Myristoyltransferase Inhibitors

Abstract

N-Myristoyltransferase (NMT) is a cytosolic monomeric enzyme present in eukaryotes such as fungi and protozoa, but is not found in prokaryotes. The attachment of a 14-carbon saturated fatty acid, myristate, from myristoyl-CoA (14:0 CoA) to the N-terminal glycine residue in a specific set of cellular proteins is commonly called protein N-myristoylation. The myristoylation reaction catalyzed by the enzyme myristoyl CoA:NMT is both necessary for the growth of various organisms and conclusive for cellular proliferation. Therefore, NMT has been identified as a novel and promising target for antifungal, antiparasitic, and anticancer agents, and a large number of potent NMT inhibitors with antifungal, antiparasitic, and anticancer activities have been reported. Herein we describe recent advances in the discovery of NMT inhibitors. We introduce not only the functions of NMT, but also some representative natural and synthetic inhibitors, with a focus on their biological activity, selectivity, and structure-activity relationship (SAR) information. In particular, inspiration from NMT inhibitor structures and the future direction of these compounds are highlighted.

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

“…Although numerous NMT inhibitors have been developed as antiviral, antifungal or antiparastic agents (29), only a limited number of inhibitors including COPP24 and “Compound 1” have been reported as anticancer agents (30, 31). NMT activity occurs via the formation of a ternary complex with myristoyl-CoA and glycine at the N-terminus of the target proteins (32).…”

Synthesis, Characterization and Antifungal Evaluation of Novel Thiochromanone Derivatives Containing Indole Skeleton

“…All the compounds were elucidated by high resolution mass spectroscope (HR-MS), 1 H-NMR, and 13 C-NMR. Table 2 is shown the reaction conditions exploration of synthetic compound 3.…”

“…1) However, effective and low toxic antifungal agents are limited. Clinically, Aspergillus fumigatus (mortality rate: 50-90%), Cryptococcus neoformans (mortality rate: 20-70%), and Candida albicans (mortality rate: 20-40%) have been identied as the most common causes of fungal infections.…”

“…14) As a result, NMT has been identified as a potential chemotherapeutic target enzyme for antifungal agents. 1) Previously, Sheng and colleagues 12) had prepared tetrahydrocarbazole derivatives ( Fig. 1) and tested their antimicrobial activity (minimal inhibitory concentration (MIC) range: 0.0156 to 64 μg/mL).…”

Design, Synthesis, Antifungal Activity and Molecular Docking of Thiochroman-4-one Derivatives

“…[9][10][11][12] NMT is a promising target enzyme 13,14) for the development of novel fungicidal drugs having a broad antifungal spectrum. Four kinds of NMT inhibitors have been reported (Fig.…”